Ten Targets for Reducing Alzheimer's Risk

Ten risk factors appeared to have a significant effect on developing Alzheimer's disease, many of which could be targeted with preventive steps, a meta-analysis suggested.

From an analysis of 395 studies, 21 clinical evidence-based suggestions to reduce Alzheimer's disease risk emerged, reported Jin-Tai Yu, MS, PhD, of Fudan University in Shanghai, China, and colleagues.

The suggestions pinpointed 10 risk factors with Class 1 Level A strong evidence, they wrote in the Journal of Neurology, Neurosurgery & Psychiatry:

• Diabetes
• Hyperhomocysteinemia
• Poor BMI management
• Reduced education
• Hypertension in midlife
• Orthostatic hypotension
• Head trauma
• Less cognitive activity
• Stress
• Depression

Nine risk factors had Class 1 Level B weaker evidence: obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation, and vitamin C, they added. Two interventions with Class III evidence were not recommended: estrogen replacement therapy and acetylcholinesterase inhibitors.

Evidence about Alzheimer's disease prevention is challenging to interpret "due to varying study designs with different endpoints and credibility," Yu noted.

"We worked with an international team of researchers, including several renowned neurologists, geriatricians, psychiatrists, psychologists, and epidemiologists, to review and analyze all current evidence in order to produce the first evidence-based guideline for Alzheimer's disease prevention," he told MedPage Today.

"Nearly two-thirds of these suggestions target vascular risk factors and lifestyle, strengthening the importance of keeping a good vascular condition and maintaining a healthy lifestyle for preventing Alzheimer's disease," he added.

"Evidence is building rapidly that modifiable risk factors play a key role in whether a person will develop cognitive decline and impairment as they age, whether that be due to Alzheimer's disease or any other dementia," observed Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer's Association in Chicago, who wasn't involved with the study.

"However, it can be difficult to separate the wheat from the chaff," Fargo told MedPage Today. "While no proposed intervention has been shown to be perfect -- we can reduce risk, but not yet eliminate risk altogether -- meta-analyses such as these are helping us hone in on some of the most important factors, as well as helping us steer clear of things that may not be as impactful."

The "ultimate gold standard" is a randomized, controlled clinical trial to evaluate whether lifestyle interventions that target many risk factors can protect cognition in older adults at increased risk of decline, like the ongoing U.S. POINTER study, Fargo added.

In their review, Yu and collaborators looked at data from 243 observational prospective studies and 152 randomized controlled trials, culled from electronic databases and relevant websites from inception until March 2019. A total of 104 modifiable risk factors and 11 interventions were included in their analysis.

Most studies (82%) recruited people without dementia at baseline, and 17% specifically constrained the sample population to people with normal cognition.

Bias in observational studies stemmed mainly from generalizability, attrition, and misclassification. In trials, performance bias, incomplete outcome data, inadequate allocation concealment, and selective outcome reporting were factors.

The findings are in line with other studies that have not shown a beneficial effect of menopausal hormone therapy on Alzheimer's disease, noted Tomi Mikkola, MD, of Helsinki University Hospital in Finland, who wasn't involved with the meta-analysis. "However, we have shown in various papers that menopausal hormone therapy has beneficial effects on vascular disease, including vascular dementia," he said.

"In my view, this outlines the difference of Alzheimer's disease and vascular dementia, although in many studies they have not been clearly separated and this is a challenge since, at a very old age, likely both may occur," Mikkola told MedPage Today. "It shows the importance to try to further study and understand Alzheimer's disease in more detail; it's likely we have missed 'the window of opportunity' at the time of the Alzheimer's diagnosis."

The suggestions that emerge from this meta-analysis should be particularly noted by non-demented but high-risk individuals -- people who carry APOEε4 or who have a high polygenic score, family history of dementia, or amyloid- positive evidence -- and their primary care physicians, the researchers wrote.

"Our study provides an advanced and contemporary survey of the evidence, suggesting that more high-quality observational prospective studies and randomized controlled trials are urgently needed to strengthen the evidence base for uncovering more promising approaches to preventing Alzheimer's disease," Yu said.

"Well-designed clinical trials also are needed to verify the effects on Alzheimer's disease of several promising interventions, including sleep improvement, smoking cessation, anti-depression management, and anti-diabetic agents," he added.

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