Abstract
Objective: Research has reported associations among selected genetic susceptibility biomarkers and risk of (a) normal cognitive aging decrements, (b) established mild cognitive impairment (MCI), and (c) sporadic Alzheimer's disease (AD). In focusing on the transitional normal-to-early MCI phase, we examine associations among three theoretically relevant polymorphisms (APOE [rs429358, rs7412], BDNF [rs6265], COMT [rs4680]) and both baseline cognitive status (MCI vs. normal aging) and two-wave (four-year) longitudinal stability or change profiles. The latter included three profiles: (a) stable as normal aging, (b) stable or chronic impairment (MCI-to-MCI), and (c) emergence of impairment (normal-to-MCI).Method: Genotyped older adults (n = 237 at baseline; age range = 64–91; 62% women) from the Victoria Longitudinal Study were examined for (a) independent and interactive associations of three genetic polymorphisms with (b) two objectively classified cognitive status groups (not-impaired controls (NIC) and MCI) at (c) both baseline and across a two-wave (four-year) longitudinal interval.Results: First, logistic regression revealed that the presence of at least one APOE ε4 allele (the risk factor for AD) was linked to greater baseline risk of objective MCI. Second, multinomial logistic regression revealed that (a) the presence of an APOE ε4 allele was associated with an increased risk of 4-year MCI status stability (chronicity), and (b) the COMT homozygous risk genotype (G/G or Val/Val) was associated with an increased risk of both MCI-to-MCI stability (chronicity) and emerging NIC-to-MCI conversion.Discussion: Both chronicity and emergence of objectively classified early cognitive impairment may be genetically heterogeneous phenomena, with influences from a panel of both normal cognitive aging (COMT) and AD-related (APOE) polymorphisms.
Highlights
The often lengthy and subtle pathophysiological changes linking normal aging and diagnosable sporadic Alzheimer’s disease (AD) are continuous, differentiable, detectable, and worthy of study as a classifiable phase in growing numbers of older adults (e.g., Albert et al, 2011; McKhann et al, 2011; Sperling et al, 2013)
Multinomial logistic regression revealed that (a) the presence of an APOE ε4 allele was associated with an increased risk of 4-year mild cognitive impairment (MCI) status stability, and (b) the COMT homozygous risk genotype (G/G or Val/Val) was associated with an increased risk of both MCI-to-MCI stability and emerging not-impaired control (NIC)-to-MCI conversion
GENOTYPE AND ALLELIC FREQUENCIES Consistent with literature indicating that APOE, BDNF, and COMT polymorphisms may be associated with lower levels of cognitive functioning in older adults (Bruder et al, 2005; Payton, 2009; Cathomas et al, 2010; Wisdom et al, 2011; Laukka et al, 2013), we informally expected that these genetic polymorphisms would show differential frequencies between the two cognitive status groups at baseline and among the four cognitive status stability groups (Brainerd et al, 2011)
Summary
The often lengthy and subtle pathophysiological changes linking normal aging and diagnosable sporadic (late-onset) Alzheimer’s disease (AD) are continuous, differentiable, detectable, and worthy of study as a classifiable phase in growing numbers of older adults (e.g., Albert et al, 2011; McKhann et al, 2011; Sperling et al, 2013). New longitudinal data have revealed evidence of varying stabilities in status, especially in MCI transitions (e.g., Albert et al, 2011; Dolcos et al, 2012; Risacher et al, 2013). This implies that MCI status may Frontiers in Aging Neuroscience www.frontiersin.org
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