Subjective Memory Complaints in APOE ɛ 4 Carriers are Associated with High Amyloid-β Burden

INTRODUCTION

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by the presence of extracellular amyloid-β (Aβ) plaques [1]. Postmortem [2–6] and Aβ imaging [7, 8] studies indicate that Aβ deposition starts decades prior to the clinical phenotype of dementia, which may explain reports of high Aβ burden in approximately 10–30% of the healthy elderly population, as burden increases with age [9–12]. These individuals with high Aβ burden and normal cognition are likely to represent individuals in the preclinical stage ofAD.

Subjective cognitive decline (SCD), a self-reported persistent cognitive decline in the absence of objective cognitive impairment, has been associated with an increased risk of incident AD [9, 13–16]. Complaints of memory, rather than another domain (subjective memory complaints; SMC), as well as carrying the apolipoprotein E (APOE) ɛ4 AD-risk allele and older age, have been incorporated in the recently published framework paper as ‘SCD plus’ features [17], proposed to be associated with a higher likelihood of preclinical AD in individuals experiencing SCD [18]. Although previous studies consistently found a higher prevalence of high Aβ burden in APOE ɛ4 carriers [19–26], mixed results were found for SMC [9, 27]. Furthermore, conflicting results were also reported for the relationship between high Aβ burden and objective measures of memory performance[11, 28–30].

A previous Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort study found no differences in Aβ burden in participants with SMC compared to those without SMC [10]. The present study represents an extension of this prior study to a supplementary cohort of cognitively normal AIBL participants who underwent an Aβ PET scan. The aim of the present study was to investigate associations of ‘SCD plus’ features including SMC, APOE genotype and older age and objective memory functioning with Aβ burden in cognitively normal elderly.

MATERIALS AND METHODS

RESULTS

On average, participants were 73 ± 7 years old with a mean MMSE score of 29 ± 1 and 164 (53%) were female. Furthermore, 103 (34%) participants were APOE e4 carrier, 28 (25%) participants showed high amyloid burden on PET and 168 (55%) participants presented with SMC. Comparing [¹¹C]PiB and [¹⁸F]Flutemetamol cohorts, there were no differences with respect to gender, education, episodic memory, Mini-Mental State Examination scores, or presence of SMC. Individuals in the [¹¹C]PiB cohort were slightly younger (71.5 ± 7.4 versus 74.3 ± 5.6) and had a higher prevalence of APOE ɛ4 carriers (41% versus 25%) and high Aβ burden (31% versus 19%). Data were pooled for the remainder of theanalyses.

Demographic and clinical characteristics of cognitively normal AIBL participants with available Aβ PET classified by Aβ burden are shown in Table 1. Fig. 1 shows representative [¹⁸F]flutemetamol PET images of low and high Aβ burden in cognitively normal participants. Participants with low or high Aβ burden did not differ based on gender, education, and Mini-Mental State Examination scores. Participants with high Aβ burden were slightly older and had a higher prevalence of APOE ɛ4 carriers compared to those with low Aβ burden. Furthermore, there was a trend toward lower composite memory scores (p = 0.08) and higher prevalence of SMC (p = 0.05) in participants with high Aβ burden. Besides, prevalence of SMC did not differ between younger and older subjects or between APOE carriers and non-carriers.

Logistic regression analyses adjusted for gender, education, and tracer showed that older age (odds ratio (OR) = 3.21, 95% confidence intervals (95% CI) = 1.68–6.14), presence of SMC (OR = 1.90; 95% CI = 1.03–3.48), and APOE ɛ4 genotype (OR = 7.49; 95% CI = 3.96–14.15) were associated with high Aβ burden (Table 2, Model 2). In contrast, lower memory score was not associated with high Aβ burden (OR = 1.07, 95% CI = 0.57–2.02). Subsequently, we entered two-way interaction terms in the multivariate model. There was a significant interaction between SMC and APOE ɛ4 genotype (p for interaction = 0.002) and between SMC and age (p for interaction = 0.08). Stratified analyses showed that in APOE ɛ4 carriers and in younger participants, presence of SMC were associated with higher presence of Aβ (OR = 4.58, 95% CI = 1.83–11.49 for APOE ɛ4 carriers; OR = 3.73, 95% CI = 1.39–10.01 for younger individuals). Contrary, presence of SMC was not associated with high Aβ burden in APOE ɛ4 non-carriers or older participants (respectively OR = 0.74, 95% CI = 0.31–1.72; and OR = 1.24, 95% CI = 0.53–2.87). When we compared SUVR’s according to APOE ɛ4 status and SMC presence, APOE ɛ4 carriers who presented with SMC showed higher [¹⁸F]flutemetamol SUVR (0.66 ± 0.15 versus 0.51 ± 0.06) and [¹¹C]PiB SUVR (1.70 ± 0.48 versus 1.40 ± 0.36; Fig. 2) compared to APOE ɛ4 carriers without SMC, and compared to APOE ɛ4 non-carriers with or without SMC, as was previously reported in the [¹¹C]PiB cohort [10].

DISCUSSION

The present study aimed to identify associations of SCD plus features SMC, APOE genotype, and older age with high Aβ burden as measured by use of amyloid PET in cognitively normal elderly. Our findings demonstrate that besides aging and APOE ɛ4 genotype, SMC was also associated with high Aβ burden. More specifically, SMC was indicative of high Aβ burden in younger participants and in APOE ɛ4 carriers.

In agreement with the recently proposed research criteria for SCD plus [17] and a previous study [35], our findings provides support for the value of older age, SMC, and APOE ɛ4 as indicators of preclinical AD, as demonstrated by their association with high Aβ burden.

In line with our findings, previous studies reported SMC as a determinant of high Aβ burden [9, 13], although results were not always consistent [27, 29]. In addition, a recently published meta-analysis reported no differences in prevalence of amyloid pathology in SMC compared to those without complaints [36]. In the present study, SMC was associated with high Aβ burden only in younger participants and APOE ɛ4 carriers. These findings underline the potential of a combination of features including SMC, APOE ɛ4 genotype, and age for identification of cognitively normal elderly with Aβ pathology.

Previous studies also reported conflicting results for the relationship between Aβ burden and episodic memory in individuals with SMC, where some studies found that lower episodic memory was related to higher Aβ burden [21, 29] while others found no such effect [11, 30]. In the present study, we found that, while SMC did show an association with high Aβ burden, objective performance on an episodic memory task was not related to Aβ pathology. As the present study was conducted in cognitively normal participants, none of them had significant memory impairment, which might explain the lack of association. These results also provide support for the notion that in the very early stages of preclinical AD, subjective experience of memory impairment may be more sensitive to decline than objective results on our currently available tests. SMC might be related to incipient AD pathology, supported by the findings of the present and other studies where participants having SMC showed higher prevalence of high Aβ burden [9, 13], which subsequently puts them at a higher risk of developing dementia due to AD.

We found an interaction between SMC and age for the association with high Aβ burden. Perhaps counter intuitively, we found that SMC are especially associated with increased risk of high Aβ burden in younger individuals. However, a previous study reported increased risk for future dementia in specifically younger patients with SMC [37]. These findings might indicate that older individuals more generally experience SMC, not specifically related to AD dementia. When SMC occurs despite a younger age, this could be an alarm signal, warranting further study.

The present findings of increased Aβ retention and a higher prevalence of high Aβ burden in APOE ɛ4 carriers, although restricted to those with SMC, are in line with previous studies [19–26] and comparable to the results from the [¹¹C]PiB AIBL baseline cohort [10]. It has been reported that in APOE ɛ4 carriers, Aβ accumulation starts at a younger age than in non-carriers [38, 39], which results in higher Aβ burden in APOE ɛ4 carriers at a certain age as found in the present study. Furthermore, the prevalence of APOE ɛ4 in the [¹⁸F]flutemetamol cohort is comparable to findings in other cohorts of healthy individuals [19–21, 23], although lower than the APOE ɛ4 prevalence in the [¹¹C]PiB cohort [10]. However, these findings can be attributed to the preferential enrichment for APOE ɛ4 carriers in the [¹¹C]PiB cohort, enrichment criteria that were not applied to the subsequent recruitment of the [¹⁸F]flutemetamol cohort.

A strength of the present study is that it was carried out in a large sample of healthy participants recruited from the PET-imaging cohorts in the AIBL study. They will be reassessed at 18-month intervals, which will enable further investigation of SMC as indicator for (preclinical) AD. A potential limitation is that the present cohort is a convenience sample, which may therefore not be a true representation of the population at large.

The present findings revealed that SMC was associated with high Aβ burden, especially in APOE ɛ4 carriers and younger subjects. This may have important implications, as it suggests that screening for SMC increases efficiency, thereby reducing screening costs, to enrich a cognitively normal elderly cohort for high Aβ burden on PET. Therefore, besides aging and APOE genotype, SMC might be an important factor for identification of healthy elderly individuals with evidence of AD pathology eligible for secondary prevention disease modifying therapies [40].