The relation of PBV and

APOE to the diagnosis of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) versus no cognitive impairment (NCI) was examined using an ordered logistic regression model. After adjusting for serum lipids and demographic measures, a higher serum PBV level was associated with a lower odds of MCI/AD (

Table 3). Specifically, each 1 SD increase in PBV was associated with about a 30% reduced odds of MCI/AD. By contrast, an

APOE ε2ε3 was associated with about a 50% lower odds of MCI/AD, and an

APOE ε3ε4/ε4ε4 was associated with nearly twice the odds of MCI/AD (

Table 3).

Because clinical diagnoses represent cutoffs across a continuum of cognition, we next examined the relation of PBV and

APOE to GCOG using a linear regression model. After adjusting for serum lipids and demographic measures, each 1 SD higher serum PBV level was associated with more than a 10% higher GCOG (

Table 3).

APOE ε2ε3 also was associated with more than a 10% higher GCOG, whereas

APOE ε3ε4/ε4ε4 was associated with more than a 20% lower GCOG (

Table 3).

Because GCOG represents a collection of somewhat dissociable cognitive domains, we next conducted a series of linear regression models to examine the relation of PBV and

APOE to the level of function in five cognitive domains; episodic memory, visuospatial ability, semantic memory, perceptual speed, working memory. Interestingly, PBV was associated with better function in all five cognitive domains with its strongest effects on episodic memory (

Table 3). Similarly,

APOE ε3ε4/ε4ε4 was associated with lower function in all five domains with its strongest effects on episodic memory (

Table 3). By contrast,

APOE ε2ε3 was associated with better performance on tests of episodic memory and semantic memory (

Table 3).

Of the variables determined to be independently associated with AD and cognition in this study, only HDL-R and PBV are potentially modifiable. We included HDL-R in our analyses based on the association of HDL-C [

39] and TC [

40] with AD, and also because of the association of

APOE lipoprotein with HDL particles [

41]. The relationship between these variables and the non-modifiable variables of age and

APOE genotype on GCOG and the probability of dementia are graphically represented in

Figure 1. The study population was normally distributed with respect to age, HDL-R, and PBV (

Figure 1G–I) and the

APOE ε2ε3//ε3ε3//ε3ε4/ε4ε4 genotype distribution (13/64/23,

Table 2) was similar to other published distributions [

3]. The mean study GCOG was -0.03 and the overall study probability of dementia was 14.5%. If cognition and dementia were considered as a continuum resulting from aging, relative to the

APOE ε3ε3 genotype, the association of an

APOE ε3ε4/ε4ε4 genotype with cognition or dementia was approximately equal to being older by 6.2 and 6.9 years, respectively, and a

APOE ε2ε3 genotype was approximately equal to being younger by about 3.9 and 7.5 years of age, respectively (

Figure 1C,F). Although a higher HDL-R is associated with higher cognition and a lower probability of dementia (

Figure 1A,D), large differences in HDL-R are required to offset the associations attributable to

APOE genotype. In contrast, relatively small differences in PBV are needed to offset the associations attributable to

APOE genotype (

Figure 1B,E). For example, the probability of dementia in

APOE ε3ε4/ε4ε4 carriers with a PBV 0.3 units higher was equal to that of

APOE ε3ε3 carriers, and with a PBV 0.6 units higher it was equal to that of

APOE ε2ε3 carriers. Considering that 0.6 units represents less than 50% of the observed 1.3 unit PBV range, the biological system underlying PBV, if pharmacologically modifiable, has the potential to have a disease-modifying effect equal to or greater than the

APOE genotype.

Modulation of the effects of age and

APOE genotype on the probability of dementia by PBV is further illustrated in

Figure 2. Probability of dementia approached zero irrespective of the genotype when the PBV index is numerically higher (

Figure 2A). Similarly, while higher age increased dementia probability, the probability of dementia approached zero irrespective of the age at higher PBVs (

Figure 2B). These results suggest that higher PBV is protective even when other risk factors are present. As expected, another well-known protective factor, the presence of

APOE ε2ε3 allele, appeared to be also shielding against the effect of age on the probability of dementia (

Figure 2C). Consequently,

APOE ε2ε3 lowered the probability of dementia by an age equivalent to approximately 16 years compared to

APOE ε3ε4/ε4ε4 carriers (

Figure 2C). In comparison, higher PBV (>1 SD), was protective against the effect of age on the probability of dementia by an age equivalent to approximately 14 years compared to lower PBV (< 1 SD) (

Figure 2D).