With September being World Alzheimer’s Month and World Alzheimer’s Day coming up on September 21, this is a good time to review some basic facts about this illness and take a look at some recent research that suggests we may have more control over our cognitive destinies than we may think.

It is said people fear Alzheimer’s disease (AD) more than they fear cancer. Perhaps this is because even though the death toll from cancer still remains high, advances over the last several decades have improved outcomes so greatly that cancer survivors—individuals who underwent successful treatment and subsequently remain cancer-free—are now relatively commonplace. It is not commonplace, however, to meet an Alzheimer’s survivor. In fact, as far as anyone knows, they are nonexistent. According to the Alzheimer’s Association, AD is the sixth leading cause of the death in the US and the fifth leading cause among people age 65 or older. One in ten people age 65 or older are afflicted, for a total of nearly six million Americans currently living with the disease, and projections for this to reach 14 million by 2050.

Pharmaceutical drugs developed for this condition have very little impact on the course of the illness. At best, they can perhaps slightly delay disease progression, while at worst, drugs studied in the past were shown to actively worsen the illness. The track record of clinical trials is so disappointing, in fact, that at least one major pharmaceutical manufacturer has essentially waved the white flag and has stopped pursuing development of drugs for AD.

The lackluster performance of most potential AD drugs may be rooted in their mechanism of action. Many of these drugs are gamma-secretase inhibitors, intended to reduce formation of the infamous amyloid plaques often implicated in the pathogenesis of the illness. However, a large and continuously growing body of research indicates that amyloid is more likely a result, rather than a cause, of the condition, and it may even be protective against oxidative damage in the brain. The amyloid hypothesis is increasingly being abandoned because it “is no longer supported by the majority of experimental evidence.” Moreover, as we covered in a past article looking at the amyloid hypothesis, there are AD patients who lack significant amyloid buildup in the brain and conversely, there are individuals who do have substantial amyloid burden yet exhibit no signs or symptoms of cognitive decline.

Looking beyond drug therapies, dietary and lifestyle interventions are showing promise for improving cognitive performance in individuals with mild cognitive impairment or mild AD. The cornerstone of these encouraging protocols is a ketogenic diet. This very low-carb, high-fat way of eating has shown enormous benefit for those with metabolic syndrome and/or type 2 diabetes, so perhaps it’s not surprising that it appears to be somewhat beneficial for cognitive impairment, as AD is now often referred to as “type 3 diabetes.” Overlap between cognitive decline and features of metabolic syndrome are so striking that the phrase “metabolic-cognitive syndrome” has been coined to indicate the strong association between the two.

The primary pathological feature of the AD brain is a substantial decrease in brain glucose metabolism. Chronic hyperinsulinemia is a major risk factor for the condition regardless of family history or ApoE4 status. This is the main rationale for using a ketogenic approach: it’s well established that even though metabolism of glucose is impaired in the AD brain, ketone metabolism is not, so raising ketone levels either via a ketogenic diet or use of exogenous ketones (typically a beta-hydroxybutyrate salt or ester) may be able to help compensate for this gap in fuel for the brain.

If AD is in fact a metabolic illness, then it stands to reason that a metabolic therapy may be required to address the pathology. Case reports of ketogenic diets, exercise, and other interventions that improve glucoregulation and insulin sensitivity, such as time-restricted eating (a.k.a. intermittent fasting), show very heartening results, including improving scores on cognitive tests such as the MoCA (Montreal Cognitive Assessment) and MMSE (Mini Mental State Exam). These results have even been observed in subjects carrying the ApoE4 gene, which is exciting because trials of MCT-oil formulations in the absence of dietary change were shown to be beneficial for AD patients who were not E4 carriers, but not for those who carry the gene.

One such report involved a 68-year-old male heterozygous for ApoE4 with dual diagnoses of type 2 diabetes and mild AD. Ten weeks of a ketogenic diet, intermittent fasting and exercise resulted in improvement in MoCA score from 23/30 (mild AD) to 29/30 (normal ≥ 26). He also had an 88% reduction in HOMA-IR, 85% reduction in fasting insulin, 24% reduction in fasting glucose, 30% decrease in HbA1c, 39% decrease in triglycerides and 35% increase in HDL, the latter two making for a 55% reduction in triglyceride/HDL ratio, a major predictor for cardiovascular disease. These improvements are quite remarkable for only ten weeks, and considering the proposed role of metabolic syndrome/hyperinsulinemia as a factor in risk for AD, this subject’s improvement in cognitive function is likely not unrelated to the substantial improvement in metabolic health. We cannot say that the latter caused the former, but the possibility is intriguing. Similar results have been observed in reports of a 71-year old female with dual diagnoses of mild AD and metabolic syndrome, as well as in a younger subject (38-year-old male, ApoE4+, with metabolic syndrome and a family history of AD who was experiencing “early stage memory problems).

Considering the role of insulin resistance, deranged blood glucose regulation, and reduced cerebral glucose metabolism in AD, compounds that address these issues may be beneficial adjuncts to ketogenic diets for the specific purpose of supporting cognitive function. Such compounds include chromium, berberine, inositol, alpha-lipoic acid, MCT oil, ketone salts or esters, ginkgo and choline or glycerophosphocholine. 

As exciting as the potential for the ketogenic way of eating is for patients with AD or cognitive impairment, it can be very difficult for them to adhere to and may cause increased caregiver burden in a situation that is already extremely taxing physically, emotionally, and financially. In such a situation, there may be a role for using exogenous ketones and/or MCT oil for positively impacting cognition and behavior in AD patients. A heartening yet bittersweet case report chronicles the experience of a middle-aged man with AD who ultimately lost his battle with the disease, but who had substantial improvements in quality of life during his last few years owing to use of coconut and MCT oils plus a ketone ester of beta-hydroxybutyrate. (The subject’s wife, a medical doctor, is now active in the research on ketones and MCTs for Alzheimer’s and other neurodegenerative diseases.)

Much research remains to be done and many unanswered questions remain, but many of the risk factors for AD are modifiable. With World Alzheimer’s Month upon us, let us move forward from the disappointments of the past and turn our attention to strategies that may hold more promise for addressing this devastating illness.