We observed a significant correlation between PBL and cerebellum telomere lengths in AD patients, but no difference in bulk cerebellum telomere lengths in AD patients relative to age-matched control subjects. Although we did not have access to matched PBL samples for our control patients, previous measurements of PBL telomeres in patients with AD found decreases of 13% [24
], 12% [26
], and 31% [27
] compared with control subjects. The 95% confidence interval for the difference between mean cerebellum telomere length in our AD cases relative to control subjects ranged from a 12% decrease to a 28% increase. Thus, if cerebellum telomeres in AD are shortened to the same extent as PBL telomeres, we should have had a reasonable chance of detecting this. However, we may have missed a small difference because of a lack of statistical power.
Our findings of correlated telomere lengths in AD PBLs and cerebella, but no apparent difference between telomere lengths in AD and control cerebella, may appear to be at odds with several reports indicating reduced telomere lengths in the PBL of individuals with AD. However, this apparent contradiction could be explained by the accelerated attrition of PBL telomeres in AD patients compared with control subjects, with a relative sparing of cerebellum telomeres from shortening in both patient populations (see hypothetical dotted line in ). In this case, PBL and brain telomere length would be correlated in both AD and control populations, brain telomere lengths would be the same in AD patients and control subjects, and PBL telomeres would nonetheless be shorter in AD. Unfortunately, we did not have access to matched PBL DNA samples for our control population, and so any proof of this idea will require additional studies.
Consistent with the idea that bulk cerebellar telomere length is not a major determinant of AD, we found an inverse correlation between age at onset of AD and cerebellar telomere length (). This relationship most likely reflects a gradual shortening of cerebellar telomeres with age, rather than a pathogenic role in AD. If bulk cerebellar telomere length were a major determinant of AD risk, there should be little or no correlation between age at onset and telomere length, because individuals would develop AD as soon as their telomeres reached a threshold length. In this case, individuals who inherited short telomeres, or had accelerated cerebellar telomere attrition during their lifetime, would develop AD earlier than those with longer telomeres.
Following this logic, if an association exists between inherited or acquired changes in PBL telomere length and the pathogenesis of AD, one would not expect to see a correlation between PBL telomere length and age at AD onset. Our data (, PBL data) are consistent with this hypothesis, because there was no significant correlation between PBL telomere length and age at onset (consistent with a threshold effect). However, our study may not have been adequately powered to detect such a correlation, if one exists.
How might telomere dysfunction be related to AD, and why would PBL telomere length be correlated with AD? As the least direct explanation for a correlation between short PBL telomeres and AD, excessive telomere shortening simply reflects a history of generalized tissue damage and inflammation (and thus increased cell turnover and telomere shortening), which in themselves may contribute to AD. As the most direct possibility, the telomere length of PBLs directly regulates the function of these circulating immune cells, which in turn modulate AD pathogenesis, as suggested by Panossian et al. [24
]. As a middle-ground possibility, PBL telomere length is correlated with telomere length in other tissues that play a more direct role in AD pathogenesis, and changes in telomere lengths affect the function of these tissues. For example, telomere lengths in endothelial cells in brain vasculature might decline with age, as they do in the endothelial cells of other tissues.
There is some support for the notion that telomere shortening and cell senescence contribute to vascular dysfunction that in turn contributes to AD. For example, telomere dysfunction contributes to age-related vascular changes [39
], as evidenced by 1) a shortening of telomeres with age in vascular endothelial cells [40
], 2) an association between athero-sclerotic lesions and senescent cells with particularly short telomeres [41
], 3) threefold higher mortality rates from cardiovascular disease in individuals with short telomeres [12
], 4) the reversal by artificial telomerase expression of atherogenic gene expression patterns in senescent endothelial cells [42
], and 5) the significance of mean leukocyte telomere length as a predictor of future coronary artery disease in middle-aged, high-risk men [4
]. Further, there are indications that vascular factors contribute to AD, including 1) shared risk factors for atherosclerosis and AD (e.g., APOE
genotype, diabetes, and hyperlipidemia), 2) the deposition of β-amyloid in brain capillaries, 3) AD risk reduction via agents (e.g., aspirin) that also reduce vascular disease, and 4) evidence that vasculature insufficiency and thrombin production upregulate amyloid precursor protein (APP) expression and the cleavage of the amyloid beta peptide from APP [44
]. Given the small contribution of vascular cells to total brain mass (approximately 0.1%), changes in telomere length in such cells would have gone undetected in our measurements of bulk cerebellar telomeres.
Regardless of how telomere function might be related to AD, PBL telomere length could provide an independent bio-marker of AD risk that could complement other biomarkers under study. We found that PBL and brain telomere length are correlated in AD. Similar correlations were reported for telomere lengths in PBL and skin fibroblasts, and among cerebral cortex, myocardium, liver, and renal cortex, indicating correlations throughout several tissues [19
]. Nonetheless, if there proves to be no difference between cerebellar telomere lengths in AD patients and control subjects, as our findings suggest, this would indicate that inherited telomere length may not be a major determinant of AD susceptibility, because cerebellar telomere length may be a relatively good indicator of inherited telomere length. Rather, the acquired shortening of PBL telomeres, which appears to be correlated with chronic stress or inflammation [49
], might underlie the correlation of PBL telomere length with AD risk.
Further studies are required to understand the mechanistic relationship between PBL telomeres and AD, and such studies may shed new light on the mechanisms of this devastating disease.