Joshua

Matyi, B.S. | Sex Differences in Neurotrophin

Genes and Risk for Alzheimers Disease
 DISCLOSURE(S)

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Investigational, or Experimental
Drug Use:
Alzheimers Disease (AD)

Women have a higher prevalence of AD compared to men.

AD is the most common cause of dementia

5.4 million individuals in the US have AD
Two-thirds of AD cases are women

Potential reasons:
Women live longer than men
Men who survive to 65 or older may be healthier
Underlying biological and genetic mechanisms that vary by sex
Neurotrophic Factors

Dysfunction in neurotrophin signaling has been implicated in

AD, with sex-dependent effects.
Brain-derived neurotrophic factor (BDNF) and nerve-growth factor (NGF)
help regulate neural processes
Disruption in neurotrophin signaling contributes to both a cholinergic
deficit and the formation of neurofibrillary tangles and plaques present
in AD
Several BDNF and NGF single-nucleotide polymorphisms (SNPs) have
been associated with AD
Presence of the minor allele of Val66Met (rs6265) was associated with
an increased risk for AD in women only
Purpose of Study

We investigated the relationship between four SNPs

involved in neurotrophin processing and risk for AD in a
population-based sample of older adults.

Furthermore, we sought to examine whether these effects

varied by sex.
Methods

The Cache County Study of Memory in Aging:

Multi-staged, population-based,
longitudinal study
5092 participants aged 65+
Primarily Caucasian; LDS faith
Initially screened with 3MS; Dementia
Questionnaire; clinical assessment
AD diagnosed using National Institute of
Neurological and Communicative
Disorders and Stroke and Alzheimers
Disease (NINCDS) criteria
Methods

Flowchart of inclusion criteria:

Participants in
Wave 1
N = 5092

Prevalent Protocol Wave 1 No

Dementia Violators Dementia
N = 359 N = 188 N = 4545

CIND/MCI Other Dementia AD Non-case

N = 690 N = 187 N = 396 N = 3272

No SNP 1 or more SNPs No SNP 1 or more SNPs

N = 19 N = 377 N = 150 N = 3122
Results

Sample characteristics:
3499 individuals, 58% female
Mean age (SD) = 74.64 (6.84)
29% had 1 or more copy of E4 allele of APOE
377 incident cases of AD

Individuals with genotype data had significantly (p < .01) higher

education levels (M = 13.30, SD = 2.88) compared to those without
genotype data (M = 12.56, SD = 2.72)
Results

Genotype frequencies by sex:

SNP Genotype Male = N, (%) Female = N, (%) Chi2 (df) P value
rs6265 G/G 963 (66.1) 1283 (64.2) 1.97 (2) 0.37
G/a 433 (29.7) 617 (30.9)
a/a 60 (4.1) 98 (4.9)
rs56164415 C/C 1282 (89.2) 1733 (88.5) 0.47 (1) 0.49
C/t 155 (10.8) 226 (11.5)
t/t 0 (0) 0 (0)
rs2072446 C/C 1317 (91.2) 1813 (91.7) 1.56 (2) 0.46
C/t 123 (8.5) 155 (7.8)
t/t 4 (0.3) 10 (0.5)
rs2289656 C/C 964 (66.9) 1293 (65.9) 1.08 (2) 0.58
C/t 416 (28.9) 596 (30.4)
t/t 60 (4.2) 74 (3.8)
Results

Risk of AD differed by sex and genotype.

rs56164415
Female carriers of minor T allele had a significant 93% higher hazard of
AD compared to male non-carriers (p < 0.05)

rs2072446
Female carriers of minor T allele had a 60% higher hazard of AD
compared to male non-carriers (p < 0.05)
Additionally, male carriers of minor T allele had a 61% reduced hazard of
AD compared to male non-carriers, although at trend-level significance
(p = 0.07)

*There were no associations between rs6265 and rs2289656 and AD risk

Results

Risk of AD differed by sex and genotype.

rs2072446 rs56164415
Conclusions

Sex is an important modifying factor for the effects of

neurotrophin gene polymorphisms regarding the risk for AD.

These results may highlight potential sex-dependent interactions:

Gonadal hormones, such as estrogens and androgens, have been shown to

modulate neurotrophin production
Lifestyle factors that contribute to neurotrophin production, such as diet and
exercise, may differ by sex
Medications (e.g. antidepressants) have also been shown to affect BDNF levels
Coauthors

G. B. Rattinger, C. Sanders, E. K. Vernon, C.

Corcoran, J. K. Kauwe, M. Buhusi, & J. T. Tschanz

Thank you for your continued support and guidance!

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