作者：Pam Harrison
出處：WebMD醫學新聞
December 23, 2009 — 根據一篇大型前瞻性世代研究，阿茲海默氏症(Alzheimer’s disease，AD)病患比較不會發生癌症，有癌症的白人病患發生阿茲海默氏症的風險較低。不過，這個研究發現僅適用阿茲海默氏症，而不適用血管型失智症(vascular dementia，VaD)。
這項研究線上發表於12月23日的神經學(Neurology)期刊，且將在1月12日印行。
華盛頓大學醫學院的Cathy Roe博士以及來自多個中心的研究夥伴發現，有任何類型的AD — 不論是單純的或混合的AD/VaD ，在校正所有相關共同變項之後，後來因癌症住院的機會減少將近60%。同樣的，校正所有相關共同變項之後，某些有癌症的研究對象，任何AD風險減少28%，白人研究對象的單純AD風險降低43%。
作者們指出，有趣的是，只有少部份研究對象有癌症和AD風險降低的反向關聯，不過，樣本數太少而無法肯定的估計。
Roe博士向Medscape Neurology表示，AD和癌症都是身體內有異常細胞生長，一種導致過多細胞死亡，另一種則是細胞生長失控，基礎科學認為，這兩種疾病可能有相同的分子路徑。這個路徑的其中一種方向失常時，造成AD發生，如果是另一個方向失常，那就使人發生癌症。這是此一關聯的可能解釋之一。
【CHS研究中有關認知的次研究】
為了進行分析，研究者使用「Cardiovascular Health Study (CHS)」這項研究中，認知次研究的資料，以探究癌症和兩種不同類型失智(包括與神經退化有關的AD以及與腦血管傷害有關的VaD)的關聯。研究對象年紀在65歲以上，接受過磁振造影以及每年一次的簡短認知測試，至多達5年。此世代的失智平均追蹤期間為5.4年，癌症平均追蹤期間為8.3年。研究開始時，世代中有5.4%診斷有AD，17.3%診斷有癌症。
研究者報告指出，在3,020名適合的研究對象中，追蹤期間內，新診斷失智者有478名，有376人因為侵犯性癌症住院，校正性別、種族、教育、年紀、抽菸和體重之後，相較於研究開始時沒有AD的研究對象，研究開始時即有AD之研究對象的癌症住院風險減少69%。
相較於研究開始時沒有癌症者，研究開始時有癌症的白人病患於追蹤期間發生AD的風險減少43%，研究者觀察發現，有這個反向關係者佔少數，但是，有癌症病史者人數本來就少(n = 29)。
癌症病史與任何VaD、單純VaD或混合型失智的診斷時間也無關聯。
表.根據失智診斷和開始時無失智，比較首次因癌症住院的時間
預測因子 | 無失智，人數 | 失智診斷，人數 | HR (95% CI) | P 值 |
單純 AD | 2107 | 71 | 0.31 (0.12 – 0.86) | .237 |
任何 AD ( 單純 AD
與混合型 AD/VaD) | 2107 | 118 | 0.41 (0.20 – 0.84) | .0145 |
混合型 AD/VaD | 2107 | 47 | 0.58 (0.21 – 1.56) | .2765 |
任何 VaD ( 單純 VaD
與混合型 AD/VaD) | 2107 | 76 | 0.89 (0.45 – 1.77) | .7441 |
單純 VaD | 2107 | 29 | 1.64 (0.66 – 4.11) | .2885 |
任何失智診斷 | 2107 | 165 | 0.70 (0.42 – 1.17) | .1730 |
AD = 阿茲海默氏症；CI = 信心區間；HR =風險比；VaD =血管型失智。
【開始時的VaD】
如同研究者討論的，開始時納入有VaD的研究對象，使他們可以探討有AD者的偶發癌症機率是否降低，因為他們在追蹤期間比沒有失智者更早死亡。之前對於CHS樣本的研究指出，VaD病患在疾病發生與死亡之間的期間，比AD患者短。
作者們寫道，同樣地，我們發現，相較於AD患者，VaD患者在開始時的評估與死亡之間的時間也比較快，兩組有失智者發生死亡的時間都比沒有失智者快。
不過，如同他們指出的，開始時有AD和偶發癌症之間的關聯，是因為AD組比沒有失智者較快死亡，VaD組應該有相似的情況，同樣地，癌症病史與發生VaD之間沒有關聯。
Roe博士指出，這些結果認為，許多癌症的發生可能和發生神經退化異常有反向關聯，最後，如果這些發現被確認，將使我們更加瞭解這些疾病的原因，並指出新的機轉與新療法的契機。
【研究限制】
Rush大學醫學中心、Rush 阿茲海默氏症中心的David Bennett醫師與Sue Leurgans博士在編輯評論中表示，該研究有一些限制，包括研究者使用醫院紀錄來瞭解偶發癌症案例，如同他們所寫的，失智病患傾向在後期有癌症診斷，有顯著較高的癌症死亡率，但是因癌症住院頻率比沒有失智者低。他們指出，這些因素都導致失智者的癌症發生率降低。
他們也認為，治療無癌症之失智病患的死亡率、以及無失智之癌症病患的死亡率，如同傳統Cox比例涉險模式中的設限事件，可能會顯著低估這些狀況之間的關聯，而出現保護效應。
另外，他們承認該研究有許多強度，探討的關聯也值得在其他世代進行研究，辨別癌症和AD之分子機轉將可導向新的治療製劑和介入方式。
國家健康研究中心、國家心肺與血液研究中心、國家神經異常與中風研究中心、國家老化研究中心、國家研究資源中心、華盛頓大學阿茲海默氏症研究中心等支持本研究。Bennett醫師擔任Neurology的編輯委員，也擔任Abbott、Krog and Partners、Navigant Consulting Inc、Partner Fund Management LP、MFS Investment Management、UBS Global Asset Management、Schering Plough Corp、Double Helix Development、Medivation Inc以及Olson Research Group等的顧問。他也接受Danone Inc和國家健康研究中心的研究支持。
Neurology. 線上發表於2009年12月23日。
Alzheimer’s Associated With Reduced Cancer Risk; AD Risk Less in Some Cancer Patients
By Pam Harrison
Medscape Medical News
December 23, 2009 — Patients with Alzheimer’s disease (AD) are significantly less likely to develop cancer over time, whereas white patients with cancer have a lower risk of developing AD, according to a large, prospective cohort study. The study's findings, however, apply only to AD and not vascular dementia (VaD).
The study was published online December 23 and will appear in the January 12 issue of Neurology.
Cathy Roe, PhD, from the Washington University School of Medicine, St. Louis, Missouri, and multicenter colleagues found that the presence of any AD — either pure or mixed AD/VaD — was associated with an almost 60% reduction in future cancer hospitalization after adjusting for all relevant covariates. Prevalent cancer in the same cohort was associated with a 28% reduced risk of any AD and a 43% reduced risk of pure AD among white subjects, again after adjusting for all relevant confounders.
Interestingly, the opposite association between cancer and reduced risk of AD was observed in minority subjects, although the sample sizes were too small for stable estimates, the authors note.
"With both AD and cancer you have abnormal cell growth — one resulting in excessive cell death and the other out-of-control cell growth — and basic science suggests that the same molecular pathways may be involved in both," Dr. Roe told Medscape Neurology. "If one pathway is out of whack in one direction it leads to AD, and if it is out of whack in another direction, it gives you cancer. This is one possible explanation for this association."
Cognition Substudy of the CHS
For their analyses, study authors used data from the Cognition Substudy of the Cardiovascular Health Study (CHS) to investigate associations between cancer and 2 types of dementia with different origins — AD, which is related to neurodegenerative processes, and VaD, which is related to cerebrovascular insults. Participants were 65 years and older and had undergone magnetic resonance imaging and annual brief cognitive testing for up to 5 years. The cohort was followed up for a mean of 5.4 years for dementia and a mean of 8.3 years for cancer. At the study outset, 5.4% of the cohort had been diagnosed as having AD and 17.3% had been diagnosed as having cancer.
"In 3020 eligible participants, there were 478 new dementia diagnoses and 376 hospitalizations for invasive cancer over the follow-up period," investigators report. For participants with AD at study onset, the risk of future cancer hospitalization was reduced by 69% compared with those who did not have AD when the study started, after adjustment for sex, race, education, age, smoking, and weight.
For white patients who had cancer at the study outset, the risk of developing AD during follow-up was reduced by 43% compared with those who did not have cancer at baseline. "The effect was in the opposite direction for minorities, but the number of minority participants with a history of cancer was small (n = 29)," the authors observe.
Cancer history was also not associated with time to diagnosis of any VaD, pure VaD, or mixed dementia.
Table. Time to First Cancer Hospitalization by Dementia Diagnosis vs No Dementia at Baseline
| Predictor | No Dementia,
No. | Dementia Diagnosis,
No. | HR (95% CI) | P Value |
| Pure AD | 2107 | 71 | 0.31 (0.12 – 0.86) | .237 |
Any AD (pure AD
and mixed AD/VaD) | 2107 | 118 | 0.41 (0.20 – 0.84) | .0145 |
| Mixed AD/VaD | 2107 | 47 | 0.58 (0.21 – 1.56) | .2765 |
Any VaD (pure VaD
and mixed AD/VaD) | 2107 | 76 | 0.89 (0.45 – 1.77) | .7441 |
| Pure VaD | 2107 | 29 | 1.64 (0.66 – 4.11) | .2885 |
| Any dementia diagnosis | 2107 | 165 | 0.70 (0.42 – 1.17) | .1730 |
AD = Alzheimer's disease; CI = confidence interval; HR = hazard ratio; VaD = vascular dementia
VaD at Baseline
As the authors discuss, inclusion of participants with VaD at baseline allowed them to investigate whether those with AD had a reduced rate of incident cancer because they died earlier during the follow-up period than those without dementia. Previous research in the CHS sample indicated that patients with VaD have a shorter interval between disease onset and death than those with AD.
"Likewise, we found that the time between baseline assessment and death was faster for those with VaD compared to those with AD, with both dementia groups dying at a faster rate than participants without dementia in this study," the authors write.
However, as they point out, had the association of baseline AD and incident cancer been due to an earlier rate of death for the AD group vs those without dementia, "then a similar effect should have been found for the VaD group," they note. Similarly, no association between cancer history and the development of VaD was found.
"These results suggest that the development of many cancers may be inversely associated with the development of neurodegenerative disorder," Dr. Roe adds, "and ultimately, if these findings are replicated, it'll tell us more about the causes of these diseases and point out novel mechanisms to look at and new avenues of treatment."
Study Limitations
In an accompanying editorial, David Bennett, MD, and Sue Leurgans, PhD, Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, thought that the study had a number of limitations, including the fact that investigators used hospital records to identify incident cancer cases. As they write, "patients with dementia tend to be diagnosed with cancer at a later stage, have significantly higher cancer mortality rates, and may not be hospitalized as frequently for cancer relative to those without dementia." All of these factors could lead to the appearance of a reduced incidence of cancer among those with dementia, they add.
They also suggest that treating cancer-free mortality among participants with dementia and dementia-free mortality among those with cancer as censoring events in a conventional Cox proportional hazards model has the potential to "markedly underestimate" the association between these conditions, giving the appearance of protective effects.
Still, they acknowledge that the study has many strengths and associations worthy of exploration in other cohorts and that the identification of molecular mechanisms linking cancer and AD "may lead to novel therapeutic targets and interventions."
The study was supported by the National Institutes of Health, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the National Center for Research Resources, and the Washington University Alzheimer's Disease Research Center. Dr. Bennett serves on the editorial board of Neurology and has served or serves as a consultant to Abbott, Krog and Partners, Navigant Consulting Inc, Partner Fund Management LP, MFS Investment Management, UBS Global Asset Management, Schering Plough Corp, Double Helix Development, Medivation Inc, and Olson Research Group. He has also received research support from Danone Inc and the National Institutes of Health.
Neurology. Published online December 23, 2009.
