Autosomal recessive genes

    Consanguinity increases the prevalence in a population of autosomal recessive genes that may have undesirable characteristics. For example, an additional 1/16 of the variation of DNA is made homozygous by the inbreeding of a marriage of first-cousins. Conversely, the probability of identifying recessive or quasirecessive susceptibility factors is enhanced by inbreeding. Childhood mortality is increased in offspring of first-cousin marriages by a factor of 1.4 to 1.7, and children born to consanguineous unions have poorer health than the offspring of nonconsanguineous unions (including malignancies, congenital abnormalities, mental retardation, and physical handicap). Curiously, there are few studies of the effects of inbreeding on the health of adults. We have hypothesized that consanguinity in the Wadi Ara community has increased the prevalence of autosomal recessive genes that are responsible, in part, for the increased prevalence of the disease.
    It has been reported that 44% of all Arab marriages in Israel are consanguineous, with a mean inbreeding coefficient of .0192 (Jaber, Shohat, Rotter, & Shohat, 1997). The inbreeding rates for Israeli Arabs may be particularly high (as compared with Egyptians or Syrians) because mobility was reduced for centuries by the Turks. At times in Arab communities, it has been required for children to marry into their own family in part to avoid sharing resources with competing family groups.

All of the known Alzheimer-related genes (on chromosomes 21, 14, 1, and 19) are dominant (chromosomes 21,14,1) or codominant (chromosome 19). There are no known genes affecting the development of AD that are recessive, perhaps because there have been few studies of AD in populations with high levels of inbreeding. De Braekeleer et al. (1989) reported an association between inbreeding and the development of AD (inbreeding coefficient 9 times higher in AD cases than in controls) in a rural population in Quebec. Studies in the Old Order Amish have found a low prevalence of disease in this inbred community, also having a low frequency of the apo E-e4 allele (.037). Inbreeding could be linked to AD through a confounding effect of education, but the association of inbreeding and education is controversial (found for a Saudi population but not for Israeli Arabs). We expect that there are recessive factors for AD because of indirect evidence: genetic modeling studies of AD in apo E-e4 negative families are unable to reject a recessive model (Rao et al., 1996).
    However, it is difficult to evaluate recessive models in outbred populations. The high prevalence we have seen in our highly inbred Arab population in Israel might be due to the inculcation of recessive AD susceptibility alleles or to a dominant gene that became frequent by founder effect.

Alzheimer's disease from which the disease occurs

Brain - soft nerve tissue, it should be protected by destroyers and poisons: stress, alcohol, narcotics, psychotropic drugs. In Alzheimer's disease brain cells atrophy and die "bundles". I had to deal with the disease up close.

First, the disease goes unnoticed: chudit people sometimes forget what happened yesterday, but remembers well what happened in childhood. However, there comes a critical moment, as a rule on the background of a stressful situation when the problem becomes obvious: the person loses touch with the outside world ceases to recognize the closest, he was haunted by delusions. There are periods of exacerbation when patients become unbearable. It is terrible, irreparable, but will have to adapt.

What does it happen?

In Alzheimer's disease in the brain is the deposition of protein in the form of "senile plaques" and the formation of neurofibrillary tangles of so-called, consisting of damaged neurons - both of these processes lead to the destruction of nerve pathways of the brain.

While still not clear what exactly causes these changes, but in recent years, scientists were able to identify specific genes responsible for human predisposition to Alzheimer's disease.

And what is interesting: the disease is more common in poorly educated people with unskilled occupations. A person with high intelligence are less likely to face the manifestations of this disease for the reason that it has a greater number of connections between nerve cells. So when the death of some cells lost the functions can be transferred to others who have not previously been involved.

Genetic and Environmental Risk Factors for Alzheimer's Disease in Arabs Residing in Israel

There is relatively little known about the distribution of Alzheimer's disease (AD) around the world. Knowledge of high- or low-prevalence foci of disease may aid our understanding of disease mechanisms. Alzheimer's disease occurs less frequently in Asia than in Europe and North America, probably because of lower allele frequency of the apolipoprotein E (apo E) e4 allele. The disease appears to be also less common in India and Africa.

There are few studies of the disease in Arabs, and few in populations with a high level of consanguinity. We have found a remarkably high prevalence of the disease in Arabs residing in Israel. In a study in Tunisia, unspecified dementia was found to be 3 times less prevalent than in the United States. Treves, Chandra, and Korczyn (1993) found a lower prevalence of presenile AD in Sephardi, as compared with Ashkenazi Jews, but more late-onset disease in Sephardi than Ashkenazi, perhaps because of lower levels of education in Sephardi. The state of Israel is comprised of about 5 million Jews and 1 million non-Jews, mostly Moslem Arabs. This Arab population of Israel is valuable for medical research because of a high level of inbreeding, large family size, high level of smoking exposure, high level of medical care available through the Israeli Health System, excellent demographic databases available from the government, absence of alcohol use because of the religious proscription, and high participation rate (>98%).

Genetic and Environmental Risk Factors for Alzheimer's Disease in Arabs Residing in Israel

There is relatively little known about the distribution of Alzheimer's disease (AD) around the world. Knowledge of high- or low-prevalence foci of disease may aid our understanding of disease mechanisms. Alzheimer's disease occurs less frequently in Asia than in Europe and North America, probably because of lower allele frequency of the apolipoprotein E (apo E) e4 allele. The disease appears to be also less common in India and Africa.

There are few studies of the disease in Arabs, and few in populations with a high level of consanguinity. We have found a remarkably high prevalence of the disease in Arabs residing in Israel.

In a study in Tunisia, unspecified dementia was found to be 3 times less prevalent than in the United States. Treves, Chandra, and Korczyn (1993) found a lower prevalence of presenile AD in Sephardi, as compared with Ashkenazi Jews, but more late-onset disease in Sephardi than Ashkenazi, perhaps because of lower levels of education in Sephardi. The state of Israel is comprised of about 5 million Jews and 1 million non-Jews, mostly Moslem Arabs. This Arab population of Israel is valuable for medical research because of a high level of inbreeding, large family size, high level of smoking exposure, high level of medical care available through the Israeli Health System, excellent demographic databases available from the government, absence of alcohol use because of the religious proscription, and high participation rate (>98%).
Consanguinity increases the prevalence in a population of autosomal recessive genes that may have undesirable characteristics. For example, an additional 1/16 of the variation of DNA is made homozygous by the inbreeding of a marriage of first-cousins. Conversely, the probability of
identifying recessive or quasirecessive susceptibility factors is enhanced by inbreeding. Childhood mortality is increased in offspring of first-cousin marriages by a factor of 1.4 to 1.7, and children born to consanguineous unions have poorer health than the offspring of nonconsanguineous unions (including malignancies, congenital abnormalities, mental retardation,
and physical handicap). Curiously, there are few studies of the effects of inbreeding on the health of adults. We have hypothesized that consanguinity in the Wadi Ara community has increased the prevalence of autosomal recessive genes that are responsible, in part, for the
increased prevalence of the disease.

It has been reported that 44% of all Arab marriages in Israel are consanguineous, with a mean inbreeding coefficient of .0192 (Jaber, Shohat, Rotter, & Shohat, 1997). The inbreeding rates for Israeli Arabs may be particularly high (as compared with Egyptians or Syrians) because mobility
was reduced for centuries by the Turks. At times in Arab communities, it has been required for children to marry into their own family in part to avoid sharing resources with competing family groups.

Linkage studies by the Boston University group and others focused on inbred Arab families have helped to locate genes for several inherited, neurological diseases, including Wilson's disease, spinal muscular atrophy, sensorineural deafness, and autosomal recessive Duchenne-like
muscular dystrophy. Of critical relevance, successes in mapping genes for Wilson's disease and deafness using inbred Arab kindreds facilitated the cloning of these genes, which were subsequently shown to have diseasecausing mutations prevalent in outbred populations from other parts of the world, including the United States.

All of the known Alzheimer-related genes (on chromosomes 21, 14, 1, and 19) are dominant (chromosomes 21,14,1) or codominant (chromosome 19). There are no known genes affecting the development of AD that are recessive, perhaps because there have been few studies of AD in populations with high levels of inbreeding. De Braekeleer et al. (1989) reported an association between inbreeding and the development of AD (inbreeding coefficient 9 times higher in AD cases than in controls) in a rural population in Quebec. Studies in the Old Order Amish have found a low prevalence of disease in this inbred community, also having a low frequency
of the apo E-e4 allele (.037). Inbreeding could be linked to AD through a confounding effect of education, but the association of inbreeding and education is controversial (found for a Saudi population but not for Israeli Arabs). We expect that there are recessive factors for AD Genetic and Environmental Risk Factors 15 because of indirect evidence: genetic modeling studies of AD in apo E-e4 negative families are unable to reject a recessive model (Rao et al., 1996).

However, it is difficult to evaluate recessive models in outbred populations. The high prevalence we have seen in our highly inbred Arab population in Israel might be due to the inculcation of recessive AD susceptibility alleles or to a dominant gene that became frequent by founder effect.
In a population-based study of AD, we have screened all elderly residents of Wadi Ara, an Arab community in northern Israel, and observed an unusually high prevalence (20.5% of those >60 years, 60.5% of those >85 years). This prevalence is higher than that found in other populations in Israel, China, Europe, or the United States, even after adjustment for
age, education, and gender, and is not due to increased frequency of the apo E-e4 allele (Corder, Saunders, Strittmatter, et al., 1993; Saunders, Strittmatter, Schmechel, et al., 1993) which is actually reduced in this community (0.035 for nondemented elders) as compared with other Caucasians.

DNA samples were collected randomly from 256 participants of the Wadi Ara study, aged 75 ± 9, 118 male, and their apo E genotype was determined by a PCR-based method (Chapman, Estupinan, Asherov, & Goldfarb, 1996). Of the 256 cases examined, 22 carried an apo E-e4 allele
(all heterozygous), including 3 of 34 with AD (apo E-e4 allele frequency 0.04), 8 of 128 nondemented elderly participants (apo E-e4 allele frequency 0.03), 7 of 56 with age-associated memory impairment (AAMI; apo E-e4 allele frequency 0.06), and 4 of 38 with other types of dementia and pseudodementia (apo E-e4 allele frequency 0.05). These data suggest that the
apo E-e4 allele is relatively uncommon in Arabs in Wadi Ara. In fact, this is the lowest frequency of apo E-e4 ever recorded. Although the possibility that it is associated with dementia was not excluded, it cannot explain the high AD prevalence in this population.

Pedigree studies showed that more than one of three of the 168 prevalent cases were from one hamula (extended family) of the 14 found in Wadi Ara. A lOcM genome scan showed significant association with a site that has been narrowed to 1.6 cM. Evidence for linkage stemmed primarily from excess homozygosity of one of the alleles for a marker in this region in the total sample of cases (15%) compared with controls (3%). The crude odds ratio of AD associated with this genotype was 5.7 (95% CI = 1.5,21.7).

The odds increased to 10.0 (1.3-75.9) after adjustment for age, sex, and systolic blood pressure. The observation of significant but different patterns of association within multiple hamulas suggests the existence of multiple recombination between the marker and the AD susceptibility locus. This genetic location notably overlaps a region showing evidence for linkage to AD in a genome scan (Kehoe et al., 1999). This location includes several genes, including a gene strongly related to lipid metabolism. We are currently working on the precise identification of the linked gene. We are also investigating the possibility that the high prevalence of AD in Wadi Ara is related to environmental risk factors and medical illness, including a high-fat diet, altered lipid metabolism, thyroid disease, smoking, hypertension, heart disease, and stroke.

DEMENTIA PREVALENCE IN EXTREME OLD AGE

Numerous researchers have extrapolated from dementia and AD prevalence rates in younger people that all centenarians should have at least some degree of cognitive impairment. Yet our studies, as well as those of other centenarian studies, indicate that approximately 20% to 30% are cognitively intact.
Dr. Silver, our lead neuropsychologist, examined a series of 74 centenarians during a 3-year period. Some of their characteristics are noted in Table 2.1, and Table 2.2 lists the neuropsychological tests performed. We are collaborating with other centenarian studies to establish norms for components of the Mattis Dementia Rating Scale and other tests.

The neuropsychological examination, as well as other phenotyping, is performed where the person lives. Specific maneuvers are performed to accommodate for hearing and vision deficits. Multiple visits are performed to prevent fatigue from factoring into the testing, and family is often invited to participate in order to help language barriers.

Table 2.3 summarizes Dr. Silver's neuropsychological test results of 74 subjects. The neuropathological findings for 14 of these participants are summarized in Table 2.4.

It is noteworthy that evidence of microvascular disease was conspicuously absent in the 14 cases found in Table 2.4. We have noted the absence of diagnoses and blood pressure measurements for many of our participants, which would predispose to vascular disease.
We are now in the process of recruiting individuals who are willing to eventually proceed to postmortem autopsy, following them longitudinally with annual detailed neuropsychological examinations. Our aim is to recruit 33 centenarians per year, who live in close enough proximity to the Massachusetts ADRC to ensure that the brain can be obtained within 4 hours of death.

TABLE 2.1 Centenarians Who Have Undergone Neuropsychological Testing
Age range 100-110 years
Gender 86% women, 14% men
Living situation 7% live alone, 26% with family, 67% in nursing homes
Country of origin 50% foreign born

Most frequent birthplaces Italy, Ireland, and Canada Education Mean = 11 years
Range = 1-20 years


TABLE 2.2 Neuropsychological Test Battery

Mini-Mental State Exam
• Mattis Dementia Rating Scale
• Boston Naming Test (CERAD)
• Trail Making Tests
A and B
• Clock Drawing
• Drilled Word Span
• Cowboy Story
(Boston-Rochester)
• Presidents since FDR
Inventory: Self report and Observer report
• Spiers' Calculations


Geriatric Depression Scale
* Telephone Interview for Cognitive Status
• Test for Severe Impairment
• Tactile Naming
• Cognition and Health History (Informant)
• Psychiatry History (Informant)
• Clinical Dementia Rating Scale
• NEO-Five Factor Personality

Intrathecal corticosteroids might slow Alzheimer’s disease progression

Anti-inflammatory drugs for treatment and prevention of Alzheimer’s disease have to date proved disappointing, including a large study of low-dose prednisone, but higher dose steroids significantly reduced amyloid secretion in a small series of nondemented patients. In addition, there is a case report of a patient with amyloid angiopathy who had complete remission from two doses of dexamethasone, and very high dose steroids are already used for systemic amyloidosis. This paper presents the hypothesis that pulse-dosed intrathecal methylprednisolone or dexamethasone will produce detectable slowing of Alzheimer’s progression, additive to that obtained with cholinesterase inhibitors and memantine. A protocol based on treatment regimens for multiple sclerosis and central nervous system lupus is outlined, to serve as a basis for formulating clinical trials. Ultimately intrathecal corticosteroids might become part of a multi-agent regimen for Alzheimer’s disease and also have application for other neurodegenerative disorders.

Epidemiological evidence suggests that drugs which counteract inflammation might have efficacy for the prevention and treatment of Alzheimer’s disease, but up to now clinical trials have failed to show any clear-cut benefits for nonsteroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine, anti-leprosy agents or prednisone. In the case of prednisone, however, it may be that much higher doses might be effective where lower doses were not. In the largest clinical trial to date, patients were given prednisone starting at 20 mg per day for one month, followed by one year at 10 mg daily and then tapering off over another 4 months. By contrast, in a series of 16 nondemented patients aged 25 to 82 who were given prednisolone 30–60 mg per day for at least month for treatment of various conditions, there was significant reduction in cerebrospinal fluid amyloid beta peptides in 15 out of 16 patients, up to about a 50% decline for patients receiving 50 and 60 mg of prednisolone. If amyloid is indeed a cause of Alzheimer’s disease, the above data suggests high dose steroids could suppress Alzheimer’s disease by reducing amyloid.

If the above line of reasoning is on the right track, it is important to note that high dose corticosteroids are already used clinically for treatment of primary systemic amyloidosis, in amounts orders of magnitude greater than those used in the Alzheimer’s disease trial. For example, in one recently published study of a regimen combining dexamethasone and interferon, patients were given several days of dexamethasone in an amount of 40 mg per day, which would be equivalent to 400 mg of prednisone daily.

Finally, there is a case report of a 64-year-old man with multiple myeloma who had a temporary remission of Alzheimer’s disease while receiving chemotherapy with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone.

Obviously megadose of anabolic steroids or cytotoxic chemotherapy as a treatment for Alzheimer’s disease would be hard to justify, but if one can knock down amyloid production, inflammation or both with corticosteroids alone, there should be at least some therapeutic effects. The key is delivering high enough doses of corticosteroids to have efficacy without devastating or killing patients with steroid-induced side effects in the process. Building on several case reports of patients with central nervous system lupus erythematosus and multiple sclerosis who responded to intrathecal prednisolone, dexamethasone, or triamcinalone after failing oral and intravenous steroids, this paper proposes that a similar therapeutic strategy could be pursued for patients with Alzheimer’s disease. Studies in rhesus monkeys and pigs indicate that that intrathecal steroids maximize biodistribution within the brain and minimize it within the rest of the body.

Genetic Correlates of Successful Cognitive Aging

IDENTIFYING GENES PREDISPOSING TO SUCCESSFUL COGNITIVE AGING

The hypothesis driving this study is that centenarians are a select group of people who have a history of aging relatively slowly and who have either markedly delayed or entirely escaped diseases normally associated with aging, such as Alzheimer's disease (AD), cancer, stroke, and heart disease.
The ultimate challenge in this area of research is to identify the genes that are associated with such a survival advantage and the ability to age so well for such a long time without cognitive impairment. We have very exciting preliminary results revealing that centenarians can be the
key to discovering these genes.
Primarily because of funding by the Institute for the Study of Aging, continue careful annual neuropsychological testing and eventual neuropathological study of the centenarian subjects.

Approximately 20% of our participants wish to be postmortem brain donors, but we anticipate
increasing this rate to 50%, again, in part, due to the generosity of the Institute. These neuropsychological-neuropathological correlations will help us better understand what disease-free aging of the brain means and what it looks like; if causes of dementia are different in the extremely old compared with younger individuals; and the type and quantity of changes in the brain that correlate with different levels of cognitive impairment.

At the same time, we are studying the centenarians for genes that may play pivotal roles in determining how centenarians markedly delay or, in some cases, escape cognitive impairment. We have obtained the largest collection of centenarian sibships in the world (N ~ 200). Genome-wide scans from these individuals were performed and the data was given to our statistics colleagues at the Whitehead Institute and Rutgers University for linkage analyses. Based upon scans of 308 individuals making up 137 families, currently we have noted statistically significant linkage to a 20 cM region on chromosome 4. A manuscript reporting these results is currently in the review process. Discovery of genes that powerfully affect processes as broad as rates of aging and/or susceptibility to diseases, such as AD and stroke, would have dramatic impact upon understanding the underpinnings of aging and could, ultimately, lead to promising targets for drug discovery.


In our attempts to locate and recruit sibships, we have enrolled five families with many members achieving extreme old age. Such clustering lends itself to linkage studies similar to those performed in families with clustering for rare diseases (such as Tay-Sachs, cystic fibrosis, and sickle-cell anemia).
In this instance, we are not looking for the cause of a disease but rather a fantastic advantage. Four of these families are described in a recent article published in the Journal of the American Geriatrics Society. Unfortunately, because there is likely to be more than one gene (or the lack of a specific mutation) increasing the probability of achieving exceptional old age, we believe that even 10 members of one family being included in a linkage study is unlikely to produce statistically significant results. However, as we include cousins and perhaps children, such studies might prove to be feasible.
In another approach to gene discovery, we have established a collaboration with gene - expression expert Steven Gullens, PhD, from the Brigham and Women's Hospital. Because we are able to obtain brain tissue at postmortem autopsy within 4 hours of death, we will provide Dr. Gullens with ideal brain tissue samples from regions of specific interest regarding AD, as well as regions that play critical roles in cognition (e.g., frontal lobe and its influence upon executive function) for differential gene expression studies. Determining which genes are active in cognitively intact participants versus those with various causes of cognitive impairment versus
other younger controls should be an efficient approach to discovering genes critical to AD pathogenesis.