Researchers dedicated to discovering
risk factors for Alzheimer
disease and other dementias
are broadening their focus to identify
genes and lifestyle factors involved in
the protection and enhancement of
longevity and cognitive health in older
adults. Three of these scientists--
George Zubenko, MD, PhD, Gary
Small, MD, and Dilip V. Jeste, MD--
reported on their research at a recent
meeting of the American College of
Genetic links to cognitive longevity
At the University of Pittsburgh School
of Medicine, Zubenko, who is a professor
of psychiatry, and his colleagues
have been conducting a systematic
genome survey to identify the locations
of particular genes that affect the likelihood
of reaching age 90 with preserved
"I would say, and I think most
people would agree, that reaching age
90 with intact mental processes is a
reasonable definition of successful
aging. We are looking for biologic and
lifestyle pathways that would lead us
there," he told Psychiatric Times.
The study, funded by the NIH, is
among the first to identify genetic links
to cognitive longevity. Each step in
reaching that goal has necessitated
overcoming substantive hurdles, according
"The recruitment of men and women
who reach 90 years of age with preserved
cognition is a major undertaking because
few people reach that age [0.5% of the
population], and for those who do, cognitive
impairment is common. The effort
on the 'front end,' including the establishment of libraries of cell lines and DNA
samples, and an electronic database to
store the resulting clinical and laboratory
information, was a monumental
task," said Zubenko, who is also an
adjunct professor of biologic sciences at
Carnegie Mellon University.
The research team recruited and
characterized 100 older adults (94 nonagenarians
and 6 centenarians) who were
cognitively normal, as reflected by clinical
evaluations and psychometric
assessments such as the Mini-Mental
State Examination and the Dementia
Rating Scale. They were matched to
100 cognitively normal young adults
(ages 18 to 25 years) with regard to sex
(50 men and 50 women in each group),
race (white), ethnicity, and geographic
location (southwestern Pennsylvania).
The genome survey was conducted
at 10 cM resolution for simple sequence
tandem repeat polymorphisms (SSTRPs)
that identify genes for successful aging
by virtue of linkage disequilibrium.
Equal amounts of genomic DNA from
the 100 older adults and 100 younger
adults were combined to create 2 individual
"pools" of DNA representing
each group. The frequency distribution
of alleles at each SSTRP of interest was
determined for the 2 groups by typing
the 2 pools and comparing the relative
abundance of each allele-specific band.
This approach, according to Zubenko
and his colleagues,1 is considerably
more efficient than typing 200 people
individually for each of nearly 400
Some preliminary results of the
study, which involved validation of the
experimental method and results for the
Y chromosome, were reported by
Zubenko and coworkers1 in 2002.
"That paper set the stage for our
subsequent genome survey, which is
now complete. The results are interesting,"
Zubenko told Psychiatric Times.
Both the preliminary and additional
results from the completed survey were
reported at the ACNP meeting.2 The
genome survey method detected the
expected elevation of the apolipoprotein-E gene (APOE) "ε2 allele frequency
and reciprocal reduction in the ε4
frequency in the older adults as
compared with the young adults. This
pattern has been associated with exceptional
longevity among American,
European, and Asian populations.
Conversely, elevation of the frequency
of the APOE ε4 allele and the reciprocal
reduction in the frequency of the
ε2 allele has been widely linked to
The genome study also detected
significant differences in the Y-linked
SSTRPs, DYS389, and DYS390. The
distributions of alleles at both DYS389
and DYS390 differed significantly
between the older and younger men.
Evidence for additional genetic loci
that selectively influence the development
of successful aging in men or
women was also observed, according
to Zubenko, and will be reported in an
upcoming journal article.
"Historically, women have lived
longer than men on average," Zubenko
said in a news release.3 "The prevalence
of numerous serious diseases differs in
men and women, and there are important
differences in age-related physiological
changes that occur between the
sexes over the lifespan. It would not be
surprising if the collection of genes that
influences the capacity to reach old age
with normal mental capacity differs
somewhat for men and women."
Disease and lifestyle factors
In the same genome study, Zubenko
and colleagues evaluated disease and
lifestyle factors such as smoking and
alcohol consumption, with the goal of
eventually exploring the interactive
effects of genes and lifestyle on successful
The older adults suffered from an
average of 8.5 medical conditions, most
frequently heart problems, hypertension,
vision and hearing problems, and
diseases of the digestive system. Only
1 older adult had no identified medical
conditions, while 27 young adults
reported no medical conditions. Despite
the number of medical problems among
the older adults, assessments of activities
of daily living revealed only modest
functional impairment on average.
None of the older adults had a history
of mental disorders in early or middle
adulthood. The prevalence of mental
disorders in older adults was 4%, and
all of the mental disorders in this group
had developed when the patients were 81 years or older. Major depressive
disorder was the most common mental
disorder identified in both groups.
While about 40% of individuals in both
age groups had a history of cigarette
smoking, only 1 of the older adults was
currently smoking, compared with 34
young adults. Similarly, the older adults
drank alcoholic beverages much less
frequently than the younger adults.
Eighty percent of the older adults
consumed alcohol less than once a
month, compared with 15% of the
young adults. These findings, according
to Zubenko, support previous
reports of the negative consequences
of mental disorders, cigarette smoking,
and excessive alcohol consumption on
In summing up the impact of the
study, Zubenko3 said in the news release,
"The finding that genetics, lifestyle decision
making, and their interactions may
influence the ability to reach old age
with preserved cognition is exciting.
Identifying such genetic and behavioral
factors may hold promise for better
understanding the aging process and
perhaps one day enriching or extending
the lives of other individuals."
1. Zubenko GS, Stiffler JS, Hughes HB 3rd, et al.
Genome survey for loci that influence successful
aging: sample characterization, method validation,
and initial results for the Y chromosome. Am J Geriatr
2. Zubenko GS. Successful aging: a neuropsychiatric
entity. Paper presented at: 44th Annual Meeting of
the American College of Neuropsychopharmacology;
December 11-15, 2005; Waikoloa, Hawaii.
3. American College of Neuropsychopharmacology.
New research examines genetics of successful aging.
News release, December 12, 2005.
4. American College of Neuropsychopharmacology.
New study finds that older Americans may improve
memory by exercising their brains and bodies. News
release, December 12, 2005.
5. Small G. Effects of a 14-day healthy aging lifestyle
program on brain function. Paper presented at: 44th
Annual Meeting of the American College of
Neuropsychopharmacology; December 11-15, 2005;
6. Small G. The Memory Prescription: Dr. Gary Small's
14-Day Plan to Keep Your Brain and Body Young.
New York: Hyperion; 2004.
7. Small G. The Memory Bible: An Innovative Strategy
for Keeping Your Brain Young. New York: Hyperion;
8. Shoghi-Jadid K, Small GW, Agdeppa ED, et al.
Localization of neurofibrillary tangles and betaamyloid
plaques in the brains of living patients with
Alzheimer disease. Am J Geriatr Psychiatry.
9. American College of Neuropsychopharmacology.
New study shows successful aging a question of "mind
over matter." News release, December 12, 2005.
10. Jeste D. A psycho-bio-social study of successful
aging among community-dwelling seniors. Paper
presented at: 44th Annual Meeting of the American
College of Neuropsychopharmacology; December 11-
15, 2005; Waikoloa, Hawaii.