Influence of family history of dementia in the development and progression of late-onset Alzheimer's disease

INTRODUCTION

Family history of dementia, together with age, female sex, and carrying one or two copies of the apolipoprotein E (APOE) e4 allele are considered the strongest risk factors for developing late-onset Alzheimer's disease (AD). Although AD has no recognizable Mendelian pattern of inheritance, having close relatives (parents or siblings) with dementia has been associated with a greater risk for developing the disease and an earlier age at onset [Silverman et al., 1994; Payami et al., 1997; van Duijn et al., 1991; Green et al., 2002; Jayadev et al., 2008; Bendlin et al., 2010; Mosconi et al., 2010]. The chances of developing AD associated with a family history of dementia may also vary depending on which or how many family members are affected. Compared with the general population and individuals with only one parent affected, those with both parents affected appear to be at higher risk for AD (van Duijn et al., 1991; Jayadev et al., 2008; Mosconi et al., 2010]. The gender of the affected parent also seems to be a relevant factor. Having a mother with dementia appears to increase the risk of developing AD [Mosconi et al., 2010] and is associated with more AD-typical bio-markers changes [Honea et al., 2012].

APOE e4 is a recognized genetic factor involved in AD development. A single APOE e4 allele in heterozygotes is associated with a two- to threefold increased AD risk, and having two copies in homozygotes is associated with a fivefold or more increase, a pattern consistent with semi-dominant inheritance. In addition, each inherited APOE e4 allele lowers the onset age by 6–7 years [Reitz and Mayeux, 2014]. Recently it has been calculated that lifetime risks for AD conferred by APOE e4/e4 homozygous genotype is roughly 30% by age 75 and >50% by age 85 [Genin et al., 2011]. These values clearly indicate that APOE is not a simple risk factor, but it should be considered a major gene for AD susceptibility. However, despite numerous studies, determining the extent to which familial aggregation of dementia can be explained by family segregation of the APOE e4 risk allele has been elusive. The overall epidemiological data suggest that it is responsible only in part for the risk associated with a family history of dementia [Duara et al., 1996; Payami et al., 1997; Devi et al., 1999; Huang et al., 2004; Donix et al., 2012a]. Recently, magnetic resonance imaging (MRI) studies and image analysis suggest a substantial APOE e4 independent effect of family history on brain structure, supporting the hypothesis that FH-related effects are often dissociable from APOE e4-related effects [Donix et al., 2012a]. Certainly, being AD a complex disease, other risk factor genes may affect to different degrees the chances of developing AD susceptibility and may be at the basis of family aggregation, but their effect is small and difficult to single out.

Even environmental factors can give rise to family history of dementia, since lifestyle, dietary habits, and socioeconomic status are shared by family members and can be passed on from parents to offspring. Family health habits and behaviors, including smoking, poor nutrition in childhood which limits brain growth, and lack of mental activity, may all result in an increased “familial” risk of dementia in adult life [Borenstein et al., 2006]. The overall familial risk for AD will depend on a complex interplay among the environment experienced throughout the life course and susceptibility genes.

In the present investigation, we asked whether FH (degree of relationship and number of relatives) increases the risk of AD development and influences disease severity (age at onset and cognitive impairment) and, in particular, among first degree relatives, we analyzed the differences between having affected parents or siblings. In addition, we investigated whether FH is a risk factor for developing AD independent of carrying the APOE e4 risk allele, or the risk genotypes of nine other AD susceptibility genes [ESR1 (estrogen receptor 1), PPARG (peroxisome proliferator-activated receptor-gamma), CYP19 (aromatase), CHAT (choline acetyltransferase), TP53 (tumor protein P53), TP73 (tumor protein P73), FSHR (follicle-stimulating hormone receptor), P21 (cyclin-dependent kinase inhibitor 1a), CYP17 (cytochrome P450c17α)] previously investigated in this AD patient sample and turned out to be involved in AD occurrence [Corbo et al., 2006, 2009, 2011, 2014; Scacchi et al., 2007, 2009a, 2009b, 2013]. The role of some relationship measures (number of affected relatives) in the AD susceptibility has been scarcely studied before, as well as the difference among first-degree relatives (parents and siblings). The study of the possible influence of FH on quantitative traits reflecting disease severity such as age at onset and cognitive impairment may help to clarify the overall picture. Finally, trying to explain the familial aggregation of AD, for the first time at our knowledge, the analysis was extended to genes other than APOE.

MATERIALS AND METHODS

RESULTS

Table I presents the characteristics of the AD patients and controls with an affected relative (one or more) (FH+) or not (FH−). Nearly one-third (31.4%) of the AD patients had a family history of dementia. There were no significant differences in age, sex, age at AD onset, or MMSE scores between these two groups. The proportion of APOE e4 allele carriers was higher among the FH+AD patients (49.6% vs. 38.9%; P = 0.04). FH was reported by 13.8% of the controls, and there were no significant differences in age, sex, and proportion of APOE e4 carriers between controls FH+ and controls FH−. The difference in FH prevalence between the AD patients and the controls was highly significant (P = 0.0002), and the crude OR for AD conferred by FH was 2.87 (95%CI 1.6–5.1). Although control sample size is not large, post hoc power analysis revealed that the observed power of the test (1-β = 0.98, α = 0.05, two-tailed) is higher than the recommended value of 0.80 according to Cohen [1992].

To determine whether FH role in AD susceptibility was somehow linked to carrying the APOE e4 allele, the main genetic AD risk factor, the overall sample (n = 529) was stratified into two subgroups of subjects carrying or not the APOE e4 allele. FH was found to be an important risk factor for AD for both non-carriers of APOE e4 (n = 323, crude OR = 2.5, 95%CI:1.2–4.9; P= 0.009) and APOE e4 carriers (n = 197, crude = OR 3.7, 95%CI 1.04–12.9; P = 0.03). Logistic regression analysis to evaluate the effect of FH on AD susceptibility after adjusting for age, sex, and carrying or not the APOE e4 allele confirmed that having FH was associated with an increased risk of developing AD (OR = 2.71, 95%CI: 1.44–5.09; P = 0.002) independent of carrying the APOE e4 allele (OR = 2.61, 95%CI: 1.53–4.44; P = 0.0004) (Table II).

In previous studies on this AD patient sample, nine other genes (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) were found associated with susceptibility to developing AD [Corbo et al., 2006, 2009, 2011, 2014; Scacchi et al., 2007, 2009a, 2009b, 2013]. No difference in the distribution of risk genotypes for any these genes was observed between the FH+ and the FH− AD patients [CHAT rs2177369, P = 0.95; CYP17 rs743572, P = 0.80; CYP19 rs4646, P = 0.57; ESR1 rs2234693, P = 0.17; FSHRrs6165/rs6166, P = 0.77; P53 rs1042522, P = 0.60; P73rs 3765728, P = 0.92; P21rs1059234, P = 0.71; PPARGrs1801282, P = 0.74).

Detailed information on the number of relatives with dementia and the degree of relationship of the affected relatives with the proband was collected from a subset of subjects. Among the FH+ AD patients, 69% had one relative, 22% had two relatives, and 8.2% had more than two relatives with dementia. Table III reports the distribution of APOE genotypes among the AD patients by number of affected relatives. Despite the small sample size, there was a significant trend for a higher frequency of non APOE e4 genotypes (APOE e3-e3 and e3-e2) among the AD patients with one or two relatives with dementia and for a higher frequency of APOE e4 carrying genotypes among the AD patients with a higher number of relatives with dementia (χ-square for trend 4.7; P = 0.03). Logistic regression analysis to test whether having relatives with dementia (0 relatives, 1 relative, ≥2 relatives) was associated with increased AD risk showed that, after adjusting for age, sex, and carrying APOE e4, having one relative with dementia was associated with a higher risk of developing AD (OR = 3.0, 95%CI: 1.3–7.1; P = 0.01) but having ≥2 relatives with dementia seemed not (OR = 1.9, 95%CI = 0.6–6.0; P = 0.3). No difference in age at AD onset or cognitive impairment (mean MMSE score) was observed when the AD patients were stratified by number of relatives with dementia (Table IV).

Data on the degree of relationship of affected relatives with the proband were collected for 97 subjects. Table V reports the data for the AD patients with affected first-degree relatives (n = 87): 70% had a parent (one or both) and 30% had a sibling (one or more) with dementia. The mother was affected in 37% of cases; the affected mother-to-father ratio was 1.7:1 in patients with one affected parent (Table V). Logistic regression analysis showed that, after adjusting for age, sex, and carrying or not APOE e4, having a first-degree relative (parent or sibling) with dementia was associated with a higher risk of AD (OR 2.9, 95%CI 1.3–6.4; P = 0.009) and having a parent with dementia was associated with a significant risk of AD (adjusted OR 2.7, 95%CI 1.1–6.2; P = 0.02), whereas having siblings with dementia was not (adjusted OR 1.7, 95%CI 0.2–14.7; P = 0.6). No difference in the distribution of APOE e4 carrying genotypes was observed between the AD patients having parents and siblings with dementia (P = 0.75).

The mean age at AD onset was similar in the AD patients with or without an affected first-degree relative (P = 0.19), but onset occurred significantly earlier in the AD patients with an affected parent (73.6 ± 6.8 years) than in those with an affected sibling (77.2 ± 5.7; P = 0.02) (Table V). AD patients with both parents or with only the mother affected had the earliest age at AD onset but not significantly different. The difference in AD onset age was still significant in the subset of AD patients not carrying the APOE e4 allele (n = 46, P = 0.02), and it was present (albeit not significant) among those carrying the e4 allele (n = 41, P = 0.28).

There was no difference in mean cognitive impairment (MMSE score) between the AD patients with or without an affected first-degree relative (P = 0.26); however, MMSE scores were significantly lower in the AD patients with an affected parent than in those with an affected sibling (17.4 ± 5.1 vs. 20.0 ± 3.6; P = 0.02). The greatest cognitive decline was observed in the AD patients with an affected mother. The difference in cognitive decline remained significant only in the subset of AD patients carrying the APOE e4 allele (n = 41, P = 0.008) (Table V).

DISCUSSION

We reviewed the data on the family history of dementia in a well-studied sample of AD patients and controls to determine what effect it may have on the risk of developing AD. Consistent with previous studies [van Duijn et al., 1991; Silverman et al., 1994; Payami et al., 1997; Green et al., 2002; Jayadev et al., 2008; Bendlin et al., 2010; Mosconi et al., 2010], our findings suggest that a family history of dementia (FH) increases the risk of AD.

Since the APOE e4 allele is a recognized genetic risk of AD, we asked whether the higher AD risk associated with FH is somehow related to carrying or not the APOE e4 allele. As FH appeared to be associated with a higher AD risk in both the subset of APOE e4 carriers (crude OR = 3.7) and the subset of non APOE e4 carriers (crude OR = 2.5), our data, as confirmed by logistic regression, support the hypothesis that the higher AD risk associated with FH is independent of that conferred by carrying the APOE e4 allele. Study results have been mixed but some have suggested that FH is a risk factor for dementia, independent of carrying the APOE e4 allele, while others have found a strong interaction between carrying APOE e4 and the higher AD risk associated with FH [Duara et al., 1996; Payami et al., 1997; Devi et al., 1999; Huang et al., 2004; Donix et al., 2012a]. Recent neurobiological studies showing that FH and APOE e4 may exert specific effects on structural brain characteristics and cognitive performance [Donix et al., 2012a, 2012b] have furthered the hypothesis that the effects of APOE e4 and FH on AD development are independent of one another and do not completely overlap. Nevertheless, our finding that FH+ AD patients are more likely to carry the e4 genotype than FH− AD patients (49.6% vs. 38.9%) suggests that carrying it may at least partly explain family aggregation of dementia. In line with this hypothesis is our observation that the frequency of the APOE e4 carrying genotypes tended to increase with the number of relatives with dementia. Since the APOE e4 allele is the strongest hereditary risk factor of AD, it is conceivable that the greater the familial aggregation, the greater the probability that this is due to transmission of APOE e4.

The question now arises as to the role FH plays in the non APOE e4 carriers, given the finding of a high frequency of non e4 carriers among the AD patients with one or two relatives with dementia. This result strongly suggests that susceptibility genes other than APOE may contribute to the higher AD risk associated with FH. Furthermore, because the frequency of the APOE e4 allele in the Italian population is low (0.09) [Corbo and Scacchi, 1999] and the APOE e4 carrier proportion among Italian AD patients is relatively lower (42.3% in the present study) than in other populations [Crean et al., 2011], the action of other risk genes may be implicated in increasing the risk of disease. For this very reason we examined other genes that were previously found to be involved in AD occurrence in the same sample. However, the distribution of the risk genotypes of nine AD susceptibility genes did not differ between the FH+ and the FH− AD patients, indicating that none of these genes contributed significantly to familial clustering of the disease. As the risk associated with these genes is far smaller than that associated with the APOE e4 allele, the sample size may not have been adequate to detect their contribution to the genetic component of a family history of dementia. In addition, the concomitant action of non genetic factors should not be underestimated, since family members often share the same environment, lifestyle, and education levels. Taken together, both environmental and genetic factors may contribute to the composition of the risk factor “family history.”

Analysis of the AD patient subset for which we had detailed information on FH (number of affected relatives and degree of relationship of relatives with dementia) revealed that having an affected first-degree relative rather than an affected relative (various degrees of relatedness) is associated with a slightly higher AD risk, but not really different as shown by the confidence interval overlap (OR 2.9, 95%CI 1.3–6.4 vs. OR = 2.71, 95%CI: 1.44–5.09). Further analysis of the AD patients with affected first degree relatives showed that having parents with dementia was a significant risk for developing AD but having affected siblings was not. This finding goes some way to explain the somewhat odd result we found when we examined the risk of AD associated with the number of affected relatives. One would generally expect that having multiple relatives with dementia would confer a higher risk of AD than having only one affected relative, yet we observed that having only one affected relative was associated with an increased risk of AD, but in most cases (63%) the only affected relative was a parent. However the low sample size of subjects with multiple relatives with dementia, could also explain the negative result.

When we examined the effect of having FH or not on several parameters that reflect AD severity, we found no difference in age at AD onset or cognitive impairment between the AD patients with or without FH. Among the FH+ AD patients, having an affected parent was more strongly associated with earlier AD onset age and greater cognitive impairment than having an affected sibling, whereas the number of affected relatives had no effect on either of these variables.

Our data are consistent with previous studies showing that AD patients with an affected first-degree relative are at higher risk of developing AD than the general population [van Duijn et al., 1991; Duara et al., 1996; Payami et al., 1997; Jayadev et al., 2008]. The majority of studies have focused on AD patients with affected parents, and having an affected parent was generally associated with an increased risk of developing AD and earlier age at onset [Payami et al., 1997; Jayadev et al., 2008; Mosconi et al., 2010]. In general, these effects were more pronounced in the AD patients with both parents affected [Jayadev et al., 2008]. Few studies to date have attempted to differentiate the between the risk of AD in individuals having affected parents or siblings. One study [Huang et al., 2004] which analyzed parents and siblings separately reported a higher AD risk in AD patients with an affected sibling than in those with an affected parent, but the risk was associated with carrying the APOE e4.

Finally, our data indicate a high prevalence of maternal history of dementia among AD patients. The mother-to-father ratio of 1.7 is slightly lower than that reported in previous studies [Mosconi et al., 2010] which examined family history of AD and not of dementia. Indeed, the mother is affected in approximately 20% of all late onset AD cases. Our findings are shared by other observations [Mosconi et al., 2010] that, as compared with AD patients having an affected father, a maternal FH of dementia was associated with greater cognitive decline and earlier age at onset of AD in the offspring. Furthermore, brain imaging studies have shown that healthy individuals with a maternal history of AD, but not with a paternal family history, show a typical phenotype characterized by alterations in brain glucose metabolism in the same brain regions as clinical AD patients and more AD-typical biomarker changes [Mosconi et al., 2010; Honea et al., 2012]. The phenomenon may also have a demographic explanation, supposing that mothers have a greater chance of developing dementia than fathers due to longer female life expectancy. However, the above data suggest that biological mechanisms may be involved in the high prevalence of maternal history of dementia among AD patients.

In conclusion, the results of this study provide further evidence to the hypothesis that having a family history of dementia is a risk factor for AD, independent of the presence of the APOE e4 allele, and show a clear difference in the risk conferred by having parents or siblings affected, in development and the progression of the disease.