Neuroscience & Neurology

Alzheimer’s Disease - Prevention or Delay by Altering Lifestyle?

August 11, 2006 | By Shaheen E Lakhan, MS, MEd, PhD | Bookmark and Share | 1 Comment

Neuroscience and Neurology Category We now know several genes involved in the origin of Alzheimer’s disease (AD). Thus, we are now in an era where genetic testing may prove useful to complement diagnosis in individuals that may have Alzheimer’s disease, in the early detection of the disease in patients with mild cognitive deficits, and for predicting onset of the disease in those that do not have any symptoms currently. Indeed, it is now pertinent to ask the question: Can you prevent or delay Alzheimer’s disease (AD) if you changed your lifestyle?

AD is the most common cause of dementia in the United States. It will become even more common in the coming decades, as the number of elderly in the population increases. The search for new genes and genetic markers for AD is critical for identifying risk and improving the understanding of the disease’s molecular pathophysiology.

Indeed, the unearthing of AD genes, even those mutations that cause very rare cases of early-onset AD, helped inform our understanding of the amyloid hypothesis. It also help channel the search for effective treatment in the appropriate direction and opened the way for understanding the roles of new non-genetic factors in AD, behaviors or conditions that can be altered to reduce the risk of developing AD.

Alzheimer’s disease is a genetically complex and heterogeneous disorder mostly affecting the elderly, with just about 5% patients affected by bthe condition being less than 60 years old at onset. In individuals with this early-onset Alzheimer’s disease, autosomal dominant inheritance is often involved. We now know that three genetic defects cause early-onset Alzheimer’s disease in families.

The first gene genetically linked with this form of Alzheimer’s disease was the amyloid precursor protein (APP) gene on chromosome 21, with at least six different pathogenic mutations influenced by APOE genotype. The second gene is Presenilin-1 (PSEN1) on chromosome 14, with 50 different Alzheimer’s disease mutations that account for most of Alzheimer’s disease before age 50 and does not seem to be modified by APOE genotype. The third is Presenilin-2 (PSEN2) on chromosome 1 for which only two different familial Alzheimer’s disease mutations have been identified. It may be modified by APOE genotype.

On the contrary, late-onset Alzheimer’s disease, which develops after age 60, has been associated with genetic risk factors, rather than causative genes, the only confirmed genetic risk factor being the 4 allele apolipoprotein E gene (APOE-4) on chromosome 19, which has three normally occurring alleles, named 2, 3, and 4. Finding genes that add to the risk of developing the disease is hard because the condition is common, especially at advanced ages making chance familial clustering quite possible. Multiple genetic and non-genetic Alzheimer’s disease risk factors may actually occur in a single family.

Besides, since it occurs very late in life, many patients do not survive the age of risk of AD, hence assessment of its familial pattern is difficult. Other causes of cognitive decline, for example, stroke are commoner in older than younger persons, hence more likelihood of diagnostic errors. Current research indicates that APOE may act primarily as a modifier of age at onset in otherwise susceptible patients.

Observations of identical twins discordant for Alzheimer’s disease or with large differences in age at onset indicate that environmental factors are also involved in the development of AD.

Some health and lifestyle changes can lower the risk of developing AD. There is increasing evidence to show that some of the same risk factors that promote heart disease and stroke may promote, or at least worsen, the course of AD. Thus, the presence of cerebrovascular disease may predict a more rapid course in patients with dementia. Elevated midlife cholesterol, diabetes, and high midlife systolic blood pressure are also risk factors for developing AD. Changing your lifestyle to prevent these conditions might also be helping you prevent AD in the future.

By: Dr. George B. Obikoyz
Editor: Shaheen Lakhan

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Gerta Farber
February 13, 2008 | Permalink

Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH. Alzheimer’s disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci. 2008 Jan 2 ; 28(1):3-9. Pubmed Abstract

Comments on News and Primary Papers

Comment by: Lary Walker, ARF Advisor
Submitted 7 January 2008

The developing brain is particularly sensitive to environmental insults, including infection, radiation, and toxins. Because the brain is still growing, differentiating, & establishing connections at this time, such hazards can influence brain structure and function throughout the lifespan. For example, the risk of schizophrenia, a disorder that generally emerges in early adulthood, appears to be increased by specific maternal infections prenatally (Brown, 2006). Relatively little research has addressed the question of whether Alzheimer disease and other age-associated neurodegenerative disorders also might be promoted by brain changes incurred during development.
……. the study of Wu and colleagues opens the door for further work in this area. These researchers studied the brains of eight female cynomolgus monkeys (Macaca fascicularis), four of which were exposed to low but biologically significant levels of lead acetate for the first 400 days of life. The animals showed no obvious health impairments over the ensuing years, but postmortem evaluation of the brains at 23 years of age found elevated mRNA for Î²-amyloid precursor protein (APP)……….

These initial findings suggest - early lead exposure can promote the conditions for neurodegeneration-associated mechanisms later in life, and as such warrant further investigation. In addition, it is worth asking whether other types of early-life insult might have similar effects. Epidemiological studies could be informative in this regard, as has been the case for schizophrenia………

View all comments by Lary Walker

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Comment by: Changiz Geula (Disclosure)
Submitted 16 January 2008 Posted 16 January 2008

In this report, Wu et al. provide intriguing evidence that lead exposure during early postnatal life in female Macaca Fascicularis monkeys results in altered DNA methylation, oxidative stress, and changes related to amyloid pathology in late life…….. These observations are provocative and enhance the possibility that early prenatal and/or postnatal events play a crucial role in initiation of disease. They invoke the probability that events in early life, including lead exposure, contribute to Alzheimer disease (AD) in late life. This line of research is worthy of pursuit in a larger cohort and as epidemiological study in humans……..

View all comments by Changiz Geula

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Comment by: Gerta Farber
Submitted 24 January 2008 Posted 24 January 2008

This new study indicates “evidence for a developmental origin and environmental link for Alzheimer’s disease.” The major unresolved question is the timing and the triggering leading to the disease, but data does suggest that a pathogenesis is influenced by early life exposures, with results not significant until later in life.
Genetic celiac disease has long been associated with neurologic and psychiatric disorders. Mayo Clinic has discovered a relationship of CD and dementia. When I was diagnosed with CD 6 years ago, at the age of 75, it was also revealed that in addition to my mother’s autopsy in 1980 for AD, she possessed the gene responsible for my currently disabling CD.

I am aware that the past deaths of eight family members were attributed to “dementia,” with the four most recent of those diagnosed as AD. My sibling has currently also been diagnosed with AD, as well as possessing a genetic celiac gene.

This new evidence of an environmental trigger to AD would warrant a study of gluten toxicity as a possible foundation.

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How and when environmental agents and dietary factors affect the course of Alzheimer’s disease: the “LEARn” model (latent early-life associated regulation) may explain the triggering of AD.

Lahiri DK, Maloney B, Basha MR, Ge YW, Zawia NH.
Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. dlahiri@iupui.edu

Alzheimer’s disease (AD) is currently the most prominent form of dementia among the elderly. Although AD manifests in late adult life, it is not clear when the disease actually starts and how long the neuropathological processes take to develop AD…… The major unresolved question is the timing and the nature of triggering leading to AD. Is it an early or developmental and/or late phenomenon and what are the factors that trigger the cascade of pathobiochemical processes? To explain the etiology of AD one should consider the neuropathological features, such as neuronal cell death, tau tangles, and amyloid plaque, and environmental factors associated with AD, such as diet, toxicological exposure, and hormonal factors. …….. we propose a “Latent Early-Life Associated Regulation” (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. According to this model, environmental agents , intrinsic factors , and dietary factors perturb gene regulation in a long-term fashion, beginning at early developmental stages; however, these perturbations do not have pathological results until significantly later in life. ……….. The LEARn model may explain the etiology of AD and other neuropsychiatric and developmental disorders.

PMID: 17430250 [PubMed - indexed for MEDLINE]