Skin Cancer Linked to Dramatically Lower Alzheimer's Risk

Pauline Anderson

May 16, 2013

Results of a new study shows that having a history of squamous cell or basal cell skin cancer is associated with a reduced the risk of Alzheimer's disease (AD), on the order of 80% in older adults.

"Those who had nonmelanoma skin cancer had a dramatically reduced risk of developing Alzheimer's disease over several years of follow-up," Richard B. Lipton, MD, professor and vice chair of neurology and director, Division of Cognitive Aging and Dementia, Albert Einstein College of Medicine in Bronx, New York, and 1 of the study authors, told Medscape Medical News. "The question is, why."

The findings were published online May 15 in Neurology.

Dementia Cases

The new analysis included 1102 dementia-free patients aged 70 years or older who were enrolled in the Einstein Aging Study, a longitudinal epidemiologic study of older noninstitutionalized residents of the Bronx, from October 1993 to December 2009.

On the basis of self-reports of cancer diagnoses, researchers determined that at baseline, 109 participants had a history of nonmelanoma skin cancer (NMSC), and during an average of 3.7 years, 32 more participants developed NMSC.

Dr. Richard B. Lipton

Also during the study, 126 participants developed dementia. Of the incident dementia cases, 76 had only AD and 24 had mixed AD/vascular disease. In addition, 26 met criteria for dementia but did not have an AD diagnosis. Using diagnostic consensus criteria, researchers grouped dementias into all-cause dementia, any AD, or only AD.

Researchers used 4 different models to correct for various potential confounders. In a model that adjusted for sex, education, occupation, hypertension, diabetes, and coronary heart disease (but not APOE genetic status), NMSC substantially reduced AD risk (hazard ratio [HR] for developing only AD, 0.21; P = .031). Only 2 participants with NMSC developed only AD.

For all-cause dementia, the protective effect was diminished (HR, 0.68; P = .24).

In a model that added APOE status to other confounders, there was a substantial, but nonsignificant, reduced risk for dementia (only AD: HR, 0.18, P = .094; any AD: HR, 0.60, P = .35; all-cause dementia: HR, 0.75; P = .50).

Squamous cell and basal cell skin cancers were associated with about equal protection. Melanoma, the least common type of skin cancer, was not included because past studies have not linked it to a protective effect against AD, the researchers note.

Although skin cancer is the most common cancer among whites, it's much rarer among African Americans. When the analyses were repeated using only white participants, the NMSC continued to be associated with a reduced risk of developing only AD, but statistical confidence was reduced.

Interestingly, the study showed that participants with a history of NMSC performed better than NMSC-free participants in baseline cognitive assessments.

Opposite Conditions

In some respects, skin cancer and AD may be opposites — in cancer, certain cells divide out of control, while in AD, particular cells die. It's possible that if cells have a propensity to divide and survive, that could protect against AD, but if cells have a tendency to die, that could protect against cancer, said Dr. Lipton.

This theory is "plausible" because brain and skin cells are derived from the same embryonic ectoderm germ layer, he explained.

"I'm intrigued by the idea that some people's cells have a tendency to divide and form skin cancer, and other people have cells that tend to die and they develop Alzheimer's disease. Understanding the cellular mechanisms could lead to strategies that might protect against both skin cancer and Alzheimer's disease."

According to Dr. Lipton, there are several possible explanations for why NMSC has a cognitive protective effect. Being physically active while exposed to ultraviolet radiation from sunlight — a risk factor for NMSC — may play a role, but that seems unlikely because this would protect against vascular dementia as well as AD, said Dr. Lipton. Another possibility is that vitamin D provides some protection.

"We don't really know if this association means that there's some underlying factor that increases your risk of skin cancer and decreases your risk of AD — like the tendency of cells to divide and survive — or if there's some environmental factor that increases the risk of one and decreases the risk of the other," said Dr. Lipton.

He added that biological factors, including genetic factors, probably play a role.

It could also be that all cancers protect against AD. "There have been other studies that showed that all forms of cancer protect against Alzheimer's disease, and it's not just that if you have cancer you die young and therefore don't have the opportunity to get it; it's age-specific rates," said Dr. Lipton.

In any case, Dr. Lipton stresses that patients should take steps to avoid skin cancer.

The next research step is to measure vitamin D levels in study participants with and without skin cancer and in those who do and do not develop AD. Dr. Lipton and his colleagues also plan to see whether there's a "geographic gradient" of AD across sunny and not-so-sunny states.

As well, they hope to expand the scope of the research by including data from other centers, which might shed more light on the possible mechanisms, said Dr. Lipton.

Biological Mechanism?

For a comment on the study, Victor W. Henderson, MD, professor of health research & policy (epidemiology) and of neurology & neurological sciences, Stanford University, California, and a member of the American Academy of Neurology, called this an important and interesting study.

"There are a lot of positive things to say about the investigative team and the approach they took in trying to look at the relationship between skin cancer and Alzheimer disease," he told Medscape Medical News.

However, whether that relationship is driven by some sort of biological mechanism or a confounding association remains unclear, said Dr. Henderson.

The study does not rule out the involvement of factors unrelated to AD, he added. "Things that might induce some people to be out in the sun more — to be healthier, to have different lifestyle practices — might be associated with lower risk of developing AD, and skin cancer then becomes an irrelevant marker."

The study might have had recall bias in that some participants may not have remembered having skin cancer if they deemed it to be less important than other cancers, said Dr. Henderson.

He also found the baseline differences in intellectual function between participants who had a history of skin cancer and those who did not "worrisome" because although these differences could represent variations in underlying AD pathology, they could also reflect lifestyle factors related to higher intelligence that themselves protect against AD. "So those baseline differences can work both ways."

The study was supported by the National Institute on Aging, the Einstein Aging Study, the National Cancer Institute, and the Albert Einstein Cancer Center. Dr. Lipton reports that he receives research support from the National Institutes of Health, the National Headache Foundation, and the Migraine Research Fund; has reviewed for the National Institute on Aging and National Institute of Neurological Disorders and Stroke; holds stock options in Neuralieve Inc (a company without commercial products); serves as consultant and advisory board member for or has received honoraria from Allergan, American Headache Society, Autonomic Technologies, Boston Scientific, Bristol-Myers Squibb, CogniMed, Diamond Headache Clinic, Eli Lilly, Endo, GlaxoSmithKline, Merck, Nautilus Neuroscience, Neuralieve, and Novartis. Disclosures for coauthors are available with the original report.

Neurology. Published online May 15, 2013. Abstract

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