Increased Paternal Age is a Risk Factor For Alzheimer's Disease in the Absence of a Major Gene

Neurogenetics. 1998 Aug;1(4):277-80. Links
Paternal age is a risk factor for Alzheimer disease in the absence of a major gene.Bertram L, Busch R, Spiegl M, Lautenschlager NT, Muller U, Kurz A.
Department of Psychiatry, Technical University Munich, Germany.

We compared the parental age at birth of patients with Alzheimer disease (AD) with that of cognitively healthy control subjects. Within 206 carefully diagnosed AD patients, two groups were distinguished according to the likelihood of carrying a major gene for AD (MGAD). This likelihood was calculated by applying a Bayesian approach which incorporates data on aggregation of the disease, age at onset, and "censoring" ages within the family. All AD patients were ranked by MGAD probability. According to the sample's quartiles, two subgroups were defined representing the 52 individuals with the lowest and the 52 with the highest MGAD probability. Age at onset of dementia, education, and apolipoprotein E epsilon4 allele frequencies were not statistically different between the two groups. Fathers of patients with a low MGAD probability were significantly older (35.7+/-8.1 years) than fathers of both other groups (high MGAD probability 31.3+/-6.9 years, P=0.004; controls 32.6+/-6.8 years, P=0.04, n=50). The differences for mothers were less pronounced and not statistically significant. These findings suggest that increased paternal age is a risk factor for AD in the absence of a major gene, whereas increased maternal age and AD are associated only weakly and independently of genetic disposition.

PMID: 10732803 [PubMed - indexed for MEDLINE]





George Bartzokis,M.D.


Visiting Professor

Laboratory of Neuro Imaging,
Department of Neurology, UCLA School of Medicine
635 Charles Young Drive South, Suite 225
Los Angeles, CA 90095-7332



Education

1975-1979, BA Harvard University, Cambridge, MA
1979-1983, MD Yale Medical School, New Haven, CT
1983-1984, Internship, UCLA/WLA VA, Los Angeles, CA
1984-1987, Psychiatry Residency, UCLA NPI, Los Angeles, CA
1987-1990, Schizophrenia Research Fellow, UCLA Dept of Psychology, Los Angeles, CA


Research

Development of brain imaging biomarkers for use in diagnosis of neuropsychiatric disorders and medication development
Assessing brain maturation and degeneration trajectories over the life-span in normal populations and how neuropsychiatric disorders interact with these processes


Projects

Myelin breakdown in aging and Alzheimer's disease
In vivo quantification of age-related increases in brain iron levels
Evaluation of brain maturational trajectories in normal adults and patientss with neuropsychiatrc diseases


Skills

Quantification of brain iron levels
Quantification of limbic structures volumes
Quantification of brain myelination
Quantification of myelin integrity
Clinical trials
Administration of multidisciplinary teams


Honors

U.S. Patent, Method for Quantitatively Measuring Stored Iron in Tissue Using MRI



This quote is not from a published paper.
I had asked Dr. Bartzokis why risk of non-familial autism, schizophrenia, MS, and Alzheimer's risk increases with the age of the father at a person's birth.


"The issue is that the older man will have sperm that has undergone more divisions and therefore had more chances to have mutations.
The COMPLEXITY of the myelination process makes it more vulnerable to mutations. I am not talking of one specific mutation. Many things could MANIFEST in the myelination or myelin breakdown process because it is so vulnerable - something going slightly wrong will impact it while it will not impact bone growth or the heart. A good example is ApoE4 - whatever else it may affect, it manifests in the reduced capacity of myelin repair and earlier onset of AD."


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Charles Lee, Ph.D.

This analysis of so-called copy number variation (CNV) has now revealed some startling results.

It would seem the assumption that the DNA of any two humans is 99.9% similar in content and identity no longer holds.

The researchers were astonished to locate 1,447 CNVs in nearly 2,900 genes, the starting "templates" written in the DNA that are used by cells to make the proteins which drive our bodies.

This is a huge, hitherto unrecognised, level of variation between one individual and the next.

"Each one of us has a unique pattern of gains and losses of complete sections of DNA," said Matthew Hurles, of the UK's Wellcome Trust Sanger Institute.

"One of the real surprises of these results was just how much of our DNA varies in copy number. We estimate this to be at least 12% of the genome.

"The copy number variation that researchers had seen before was simply the tip of the iceberg, while the bulk lay submerged, undetected. We now appreciate the immense contribution of this phenomenon to genetic differences between individuals."

Evolving story

The new understanding will change the way in which scientists search for genes involved in disease.


"Many examples of diseases resulting from changes in copy number are emerging," commented Charles Lee, one of the project's leaders from Brigham and Women's Hospital and Harvard Medical School in Boston, US.

"A recent review lists 17 conditions of the nervous system alone - including Parkinson's disease and Alzheimer's disease - that can result from such copy number changes."

Scientists are not sure why the copy variations emerge, but it probably has something to do with the shuffling of genetic material that occurs in the production of eggs and sperm; the process is prone to errors.

As well as aiding the investigation of disease and the development of new drugs, the research will also inform the study of human evolution, which probes genetic variation in modern populations for what it can say about their relationship to ancestral peoples.

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285 of the approximately 3,000 CNVs are already known to be
associated with disease, and copy number variations of some of
these genes have been or are now being speculated as risk
factors for ailments such as AIDS, inflammatory bowel disease, lupus, cataracts, arterial disease and
schizophrenia.
One interesting observation that the researchers made during this study was that many of the CNVs have
population-specific characteristics and frequencies, which could explain increased prevalence of some diseases in
certain populations. For example, previous research found that the deletion of the UGT2B17 gene may lead to an
increased risk of prostate cancer in African American men. As a result of this and other research, the consortium is
expanding their studies to thousands of healthy individuals from populations outside of the HapMap collection.


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WHAT ARE THE DANGERS TO SOCIETY OF MEN FATHERING BABIES LATER AND LATER IN LIFE?
IS THE AUTISM EPIDEMIC CAUSED IN LARGE PART BY SO MANY MEN FATHERING BABIES PAST THE AGE OF 35?
IS THE DIABETES TYPE 1 EPIDEMIC ALSO CAUSED BY THE EPIDEMIC OF LATER FATHERING OF BABIES?




IS ANYONE LOOKING FOR A PATERNAL AGE EFFECT IN THE MUTATIONS TO GENES IN TYPE 2 DIABETES? OR CROHN'S, OR LUPUS, OR RHEUMATOID ARTHRITIS, OR FIBROMYALGIA, ETC. ETC.

ADVANCED PATERNAL AGE: How old is too old?
Isabelle Bray, David Gunnel and George Davey Smith
Department of Social Medicine, University of Bristol, UK
Journal of Epidemiology amd Community Health 2006;60:851-853

"Average paternal age in the UK is increasing. The public health implications of this trend have not been widely anticipated or debated. .....Accumulated chromosomal aberrations and mutations occurring during the maturation of the male germ cells are thought to be responsible for the increased risk of certain conditions with older fathers. Growing evidence shows that the offspring of older fathers have reduced fertility and an increased risk of birth defects, some cancers and schizophrenia." ......