Fat Gene (FTO) Linked to Alzheimer's Disease Risk

The relationship between obesity and risk for Alzheimer's disease is a controversial area of research.

Several studies have found a prospective increase in risk for Alzheimer's disease in those with obesity.  However, the association has been inconsistent.  Some studies have even found a reduced risk of later Alzheimer's disease in overweight populations.

One method to further investigate the possible obesity-Alzheimer's risk association is through direct genetic studies of genes known to be related to obesity.

Christiane Reitz and colleagues from the U.S. National Institute on Aging recently published this type of study in the journal PLOS One.

They focused on polymorphisms of the Fat and Obesity-Associated (FTO) gene.  The FTO gene is located on the q arm of human chromosome 15.  Polymorphisms associated with FTO intron 1, intron 2 and exon 2 have been linked to increased rates for obesity and also have some evidence of being linked to risk for Alzheimer's disease.

To study this issue in more detail, Reitz and colleagues conducted a single nucleotide protein (SNP) analysis of the FTO gene in Alzheimer's disease subjects and controls.  Two independent samples with a combined sample size approaching 3000 subjects were used in the SNP analysis. Additionally, they conducted a FTO gene expression analysis of Alzheimer's disease cases that had been confirmed by brain neuropathological analysis. 

The key finds from this genetic study were:

• Eight FTO SNP regions were linked to variation in risk for Alzheimer's disease
• Eleven FTO haplotypes were identified that significantly contributed to risk for Alzheimers's disease
• Gene expression studies in brain tissue of Alzheimer's disease subjects showed lower FTO gene expression compared to controls

The authors note their study findings "confirm the association between genetic variation in Intron 1, Exon 2 or Intron 2 in the FTO gene and AD".  (AD=Alzheimer's disease).

They propose several mechanisms for this association.  FTO gene status increases risk for hyperinsulinemia and type II diabetes, known risk factors for Alzheimer's disease.  They note a second potential mechanism where FTO gene status contributes to Alzheimer's disease by a vascular pathology (i.e. hypertension, lipid dysregulation, atherosclerosis).  Finally, they note obesity increases inflammatory markers by increasing adipokines and cytokines that may contribute to risk or severity of Alzheimer's disease.

This is an important study in the ongoing search to understand the effect of obesity on Alzheimer's disease risk.  Exploring genetic mechanisms is a promising approach to complement  epidemiological risk factor studies to advance our understanding of Alzheimer's disease. 

Photo of willet from the author's files. 

Reitz C, Tosto G, Mayeux R, Luchsinger JA, & the NIA-LOAD/NCRAD Family Study Group and the Alzheimer's Disease Neuroimaging Initiative (2012). Genetic Variants in the Fat and Obesity Associated (FTO) Gene and Risk of Alzheimer's Disease. PloS one, 7 (12) PMID: 23251365

Lifestyle Factors and Risk of Alzheimer's Dementia

The number of individuals suffering from Alzheimer's disease is rapidly increasing throughout the developed world.

A significant portion of this increase is explained by demographic trends as the Baby Boomer generation progresses through the high-risk age categories for Alzheimer's and other dementia.

It is important to understand potentially modifiable lifestyle risk factors that may stimulate a valid public health prevention program.

An important recent study examined lifestyle factors and risk for dementia among a cohort of Japanese American men.  

Gelber and colleagues followed a cohort of 3468 men over a period of 25 years.  The study focussed on the emergence of dementia including both Alzheimer's disease and vascular dementia.

The key components of the study design in this study included:

• Cohort characteristics: Men of Japanese ancestry born between 1900 through 1919 living in Oahu, Hawaii
• Dementia diagnosis: The cohort received regular neuropsychological screening with cognitive deficits prompting neurologist referral.  The study neurologist and two physicians made decisions about a diagnosis of Alzheimer's disease or vascular dementia using clinical information, neuropsychological testing, blood tests and brain imaging (CT or MRI) results. 
• Modifiable risk factor variables: BMI category, smoking status, physical activity level, dietary intake and alcohol consumption.  A global lifestyle low-risk group was identified that demonstrated the presence of a low risk on all four modifiable risk factors: BMI less than 22.6, never smoking, 3 or more hours per week of physical activity and high dietary score (more vegetable/fruit intake and moderate alcohol intake).

A total of 223 cases of dementia were identified during the follow up period.  The majority were assigned a diagnosis of Alzheimer's dementia (n=117), with vascular dementia a close second in frequency (n=78).  Twenty eight cases were given another cause for dementia.

High BMI, smoking and low physical activity all increased risk for overall dementia diagnosis with the following estimates for odds ratio of those with risk factor compared to those without:

• BMI: Odds ratio= 1.87
• Smoking: Odds ratio= 1.48
• Low physical activity: Odds ratio= 1.59

Diet score did not show a statistically significant association with overall dementia risk.

However, when specific type of dementia was examined, none of the individual lifestyle factors proved to be statistically associated with Alzheimer's disease risk.  BMI, smoking status and low physical activity were individually linked to increased risk for vascular dementia at odds ratios estimated at high levels than in the overall dementia group.

Men positive for all four lifestyle factors showed a 64% reduction in dementia risk, but this was primarily in reduction of risk for vascular dementia.

Finding no association between lifestyle factors and risk for Alzheimer's disease is somewhat discouraging.  It suggests that genetic factors, i.e. APOE gene status, may be resistant to the moderating effects of lifestyle changes.  

However, the study supports promotion of a healthy lifestyle approach in mid-life to reduce risk of vascular dementia.  Adopting all four factors in a healthy lifestyle promotes a significantly reduced risk of later dementia diagnosis.

Readers with a more detailed interest in the study can access the free full text article by clicking on the PMID link below.

Photo of burrowing owl from the author's files. 

Gelber RP, Petrovitch H, Masaki KH, Abbott RD, Ross GW, Launer LJ, & White LR (2012). Lifestyle and the risk of dementia in Japanese-american men. Journal of the American Geriatrics Society, 60 (1), 118-23 PMID: 22211390

Top Ten Brain Posts 2012: #2 Cannabis Neurosis

The number two rated Brain Post for 2012 looked at a study of the risk factors associated with the development of cannabis dependence.

This study examined genetic and psychological factors found in a group of 50 individuals with DSM-IV cannabis dependence compared to a control group without a diagnosis of cannabis dependence.

The study found two factors appeared to increase the risk for cannabis dependence.

One factor was a genetic factor involving the proenkephalin gene.  A second factor was high score on a psychological measure of neurosis.  Neurosis is a psychological factor related to risk for a variety of anxiety conditions.

The study found a particularly elevated interaction risk for individuals who had both the high risk proenkephalin genotype as well as high scores on neuroticism.  When both factors were present, risk for cannabis dependence was estimated to be about ten times higher compared to individuals without the high risk gene and with low neuroticism scores.

Legalization of marijuana in some states in the U.S. will provide a natural experiment to look at rates of problems with cannabis use.  Although limited cannabis may be used without major complications in some individuals, others may find increased access leading to development of dependence and related social, medical and behavioral complications.

Photo of Christmas ornament angel from the author's files. 

Top Ten Brain Posts 2012: #6 Opiate Deaths

The number six ranked post for 2012 on Brain Posts was "Risk Factors for Accidental Overdose". This post examined a research study from the VA that looked a series of accidental overdose deaths in Veterans between 2000 and 2006. 

Most of these deaths involved overdose with prescription or illicit drugs.  Often a combination of drugs is implicated in an accidental overdose.  

Risk factors for accidental deaths as expected included a substance abuse or alcohol abuse diagnosis.  Opiate dependence was the strongest risk factor.

However, other psychiatric disorders also increased risk for accidental overdose including: bipolar disorder, major depression, PTSD and schizophrenia.  The take home message from this study is that clinicians treating those with mental disorders should monitor patients for risk of death related to prescription and illicit use.

Another post on a related topic demonstrated that risk for accidental overdose with prescription and illicit opiates has more than doubled in the U.S. over the last decade.  Rates of opiate-related deaths vary widely between states and are highest in states with the highest rates of opiate prescription use of Lortab, Oxycontin, Vicodin and similar drugs.  Public health and law enforcement efforts are underway to reduce the number of accidental opiate overdose deaths.

Photo of Christmas tree angel ornament from the author's files.