On 2016 Aug 07, David Keller commented:

Dementia caused by elevated aluminum levels in dialysis is not Alzheimer's disease: a distinction without a difference

Professor Haenisch gave two references to substantiate her statement that "the involvement of aluminum in the etiology of dementia seems to be a matter of debate". Immediately below, I summarize what I have learned from her first reference [1]:

Lidsky points out that the clinical presentation of dementia caused by elevated aluminum levels in dialysis patients is clearly distinct from that of true Alzheimer-type dementia. He also debunks the rumor that elevated aluminum levels cause the neurofibrillary tangles in the human brain which are pathognomonic for Alzheimer disease, noting that the neurofibrillary tangles caused by aluminum exhibit a distinctly different pattern when examined carefully under immunofluorescence, proving once and for all that the form of brain damage caused by aluminum is definitely not Alzheimer disease.

These findings are noted, but are of little comfort if they merely imply that aluminum ingestion causes brain damage and dementia which cannot be classified as Alzheimer type. As a primary-care physician who must answer patients' questions about the risks of dietary aluminum, that distinction truly makes no difference to patients or to myself.

Reference

[1] Lidsky TI. Is the aluminum hypothesis dead? J Occup Environ Med. 2014;56(5)(suppl): S73-S79.

On 2016 Aug 05, David Keller commented:

Advice to avoid PPI medication is premature until major confounding by the use of aluminum antacids is eliminated

"The avoidance of PPI medication may prevent the development of dementia." So begins the widely-quoted conclusion of this study by Gomm, Haenisch and colleagues. The evidence I presented in my letter to JAMA-Neurology [1] along with its effect on their study was "addressed", as Haenisch claims, but in a manner I would characterize as completely dismissive and devoid of information.

To recapitulate, my letter pointed out that Haenisch' group had not corrected their results for chronic aluminum exposure. A recent meta-analysis of 8 case-control and cohort studies of over 10,500 subjects, showed a significant 71% increase in risk of Alzheimer dementia for subjects with chronic aluminum exposure. [2] Are these findings by Wang and colleagues not applicable for some reason?

Aluminum salts are the active ingredients of most immediately-effective over-the-counter antacids (calcium-based antacids are less effective, and antihistamines are slowly effective). Haenisch found a 44% increase in dementia for subjects taking proton pump inhibitors (PPIs), compared with subjects not taking them. However, patients taking a PPI for upper GI acid symptoms are more likely than are controls to have taken aluminum-based antacids (such as Maalox, Mylanta, Rolaids and many others). In the USA, physicians routinely inquire about the use of such antacids by patients suspected of having upper GI acid disorders.

Subjects taking PPIs logically must therefore be more likely to have a history of chronic aluminum exposure due to OTC antacid use than controls, and the 71% higher risk of dementia from their aluminum exposure is greater than the 44% increase found by Haenisch in association with PPI use. Attribution of increased risk for dementia to PPI use therefore requires correction of her dataset for exposure to aluminum antacids.

Haenisch stated "we were not able to include aluminum-containing antacids as these drugs are often not covered by the statutory health insurance in Germany". That was not how I learned epidemiology should be practiced, from a German epidemiology professor who goes out in work boots to collect the data herself if it is missing.

Therefore, the recommendation by Haenisch to avoid PPI use seems premature and should be withdrawn, as a public safety measure, until someone can truly address the following question: how much of the risk associated with PPI use is likely to be attributable to the use of aluminum-based antacids? Otherwise, we may witness an upsurge in peptic ulcer disease as patients and physicians prematurely embrace Haenisch' conclusions.

References

1: Keller DL. Proton Pump Inhibitors and Dementia Incidence. JAMA Neurol. 2016 Jun 20. doi: 10.1001/jamaneurol.2016.1488. [Epub ahead of print] PubMed PMID:27323287.

2: Wang Z, Wei X, Yang J, Suo J, Chen J, Liu X, Zhao X. Chronic exposure to aluminum and risk of Alzheimer's disease: A meta-analysis. Neurosci Lett. 2016 Jan 1;610:200-6. doi:10.1016/j.neulet.2015.11.014. Epub 2015 Nov 27. PubMed PMID: 26592479.

On 2016 Aug 03, Britta Haenisch commented:

Aluminium exposure and dementia

Keller raised the issue of aluminium ingestion and dementia risk in a letter to JAMA Neurology [1]. We would like to refer to our reply in JAMA Neurology where we addressed the comment [2]. While the involvement of aluminum in the etiology of dementia seems to be a matter of debate [3,4], this aspect is interesting to examine in further studies.

References

[1] Keller DL. Proton Pump Inhibitors and Dementia Incidence. JAMA Neurol. 2016 Jun 20. doi: 10.1001/jamaneurol.2016.1488.

[2] Gomm W, Haenisch B. Proton Pump Inhibitors and Dementia Incidence-Reply. JAMA Neurol. 2016 Jun 20. doi: 10.1001/jamaneurol.2016.1494.

[3] Wang Z, Wei X, Yang J, et al. Chronic exposure to aluminum and risk of Alzheimer’s disease: a meta-analysis. Neurosci Lett. 2016;610: 200-206.

[4] Lidsky TI. Is the aluminum hypothesis dead? J Occup Environ Med. 2014;56(5)(suppl): S73-S79.

On 2016 Jul 21, David Keller commented:

Aluminum exposure raised dementia risk by 71% in meta-analysis; PPI dementia risk confounded by aluminum-containing antacids

Dietary aluminum ingestion is theorized to be neurotoxic and play a causative role in the onset and progression of dementia. [1-3] A recent meta-analysis showed that individuals chronically exposed to aluminum were 71% more likely to develop Alzheimer disease (odds ratio, 1.71; 95% CI, 1.35-2.18).[4] Many strong antacids contain aluminum hydroxide and are often taken for years by patients with peptic ulcer disease or gastroesophageal reflux before they are prescribed proton pump inhibitors, and concurrent with their use. Gomm and colleagues [5] did not correct for the use of aluminum-containing antacids when calculating the association of dementia with proton pump inhibitor use. How much of their observed association of proton pump inhibitor use with dementia is actually due to long-term ingestion of aluminum antacids, either currently or in the past?

References

1: Bhattacharjee S, Zhao Y, Hill JM, Percy ME, Lukiw WJ. Aluminum and its potential contribution to Alzheimer's disease (AD). Front Aging Neurosci. 2014 Apr 8;6:62. doi: 10.3389/fnagi.2014.00062. eCollection 2014. PubMed PMID:24782759; PubMed Central PMCID: PMC3986683.

2: Rodella LF, Ricci F, Borsani E, Stacchiotti A, Foglio E, Favero G, Rezzani R, Mariani C, Bianchi R. Aluminium exposure induces Alzheimer's disease-like histopathological alterations in mouse brain. Histol Histopathol. 2008 Apr;23(4):433-9. PubMed PMID: 18228200.

3: Exley C. What is the risk of aluminium as a neurotoxin? Expert Rev Neurother. 2014 Jun;14(6):589-91. doi: 10.1586/14737175.2014.915745. Epub 2014 Apr 30. PubMed PMID: 24779346.

4: Wang Z, Wei X, Yang J, Suo J, Chen J, Liu X, Zhao X. Chronic exposure to aluminum and risk of Alzheimer's disease: A meta-analysis. Neurosci Lett. 2016 Jan 1;610:200-6. doi:10.1016/j.neulet.2015.11.014. Epub 2015 Nov 27. PubMed PMID: 26592479.

5: Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis [published online February 15, 2016]. JAMA Neurol. doi:10.1001/jamaneurol.2015.4791.

The above letter was published in JAMA-Neurology [6], but the reply by Gomm and colleagues failed to provide the necessary correction for aluminum antacid use.

6: Keller DL. Proton Pump Inhibitors and Dementia Incidence. JAMA Neurol. 2016 Jun 20. doi: 10.1001/jamaneurol.2016.1488. [Epub ahead of print] PubMed PMID:27323287.

On 2016 Jul 21, David Keller commented:

Aluminum exposure raised dementia risk by 71% in meta-analysis; PPI dementia risk confounded by aluminum-containing antacids

Dietary aluminum ingestion is theorized to be neurotoxic and play a causative role in the onset and progression of dementia. [1-3] A recent meta-analysis showed that individuals chronically exposed to aluminum were 71% more likely to develop Alzheimer disease (odds ratio, 1.71; 95% CI, 1.35-2.18).[4] Many strong antacids contain aluminum hydroxide and are often taken for years by patients with peptic ulcer disease or gastroesophageal reflux before they are prescribed proton pump inhibitors, and concurrent with their use. Gomm and colleagues [5] did not correct for the use of aluminum-containing antacids when calculating the association of dementia with proton pump inhibitor use. How much of their observed association of proton pump inhibitor use with dementia is actually due to long-term ingestion of aluminum antacids, either currently or in the past?

References

1: Bhattacharjee S, Zhao Y, Hill JM, Percy ME, Lukiw WJ. Aluminum and its potential contribution to Alzheimer's disease (AD). Front Aging Neurosci. 2014 Apr 8;6:62. doi: 10.3389/fnagi.2014.00062. eCollection 2014. PubMed PMID:24782759; PubMed Central PMCID: PMC3986683.

2: Rodella LF, Ricci F, Borsani E, Stacchiotti A, Foglio E, Favero G, Rezzani R, Mariani C, Bianchi R. Aluminium exposure induces Alzheimer's disease-like histopathological alterations in mouse brain. Histol Histopathol. 2008 Apr;23(4):433-9. PubMed PMID: 18228200.

3: Exley C. What is the risk of aluminium as a neurotoxin? Expert Rev Neurother. 2014 Jun;14(6):589-91. doi: 10.1586/14737175.2014.915745. Epub 2014 Apr 30. PubMed PMID: 24779346.

4: Wang Z, Wei X, Yang J, Suo J, Chen J, Liu X, Zhao X. Chronic exposure to aluminum and risk of Alzheimer's disease: A meta-analysis. Neurosci Lett. 2016 Jan 1;610:200-6. doi:10.1016/j.neulet.2015.11.014. Epub 2015 Nov 27. PubMed PMID: 26592479.

5: Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis [published online February 15, 2016]. JAMA Neurol. doi:10.1001/jamaneurol.2015.4791.

The above letter was published in JAMA-Neurology [6], but the reply by Gomm and colleagues failed to provide the necessary correction for aluminum antacid use.

6: Keller DL. Proton Pump Inhibitors and Dementia Incidence. JAMA Neurol. 2016 Jun 20. doi: 10.1001/jamaneurol.2016.1488. [Epub ahead of print] PubMed PMID:27323287.

On 2016 Aug 03, Britta Haenisch commented:

Aluminium exposure and dementia

Keller raised the issue of aluminium ingestion and dementia risk in a letter to JAMA Neurology [1]. We would like to refer to our reply in JAMA Neurology where we addressed the comment [2]. While the involvement of aluminum in the etiology of dementia seems to be a matter of debate [3,4], this aspect is interesting to examine in further studies.

References

[1] Keller DL. Proton Pump Inhibitors and Dementia Incidence. JAMA Neurol. 2016 Jun 20. doi: 10.1001/jamaneurol.2016.1488.

[2] Gomm W, Haenisch B. Proton Pump Inhibitors and Dementia Incidence-Reply. JAMA Neurol. 2016 Jun 20. doi: 10.1001/jamaneurol.2016.1494.

[3] Wang Z, Wei X, Yang J, et al. Chronic exposure to aluminum and risk of Alzheimer’s disease: a meta-analysis. Neurosci Lett. 2016;610: 200-206.

[4] Lidsky TI. Is the aluminum hypothesis dead? J Occup Environ Med. 2014;56(5)(suppl): S73-S79.

On 2016 Aug 05, David Keller commented:

Advice to avoid PPI medication is premature until major confounding by the use of aluminum antacids is eliminated

"The avoidance of PPI medication may prevent the development of dementia." So begins the widely-quoted conclusion of this study by Gomm, Haenisch and colleagues. The evidence I presented in my letter to JAMA-Neurology [1] along with its effect on their study was "addressed", as Haenisch claims, but in a manner I would characterize as completely dismissive and devoid of information.

To recapitulate, my letter pointed out that Haenisch' group had not corrected their results for chronic aluminum exposure. A recent meta-analysis of 8 case-control and cohort studies of over 10,500 subjects, showed a significant 71% increase in risk of Alzheimer dementia for subjects with chronic aluminum exposure. [2] Are these findings by Wang and colleagues not applicable for some reason?

Aluminum salts are the active ingredients of most immediately-effective over-the-counter antacids (calcium-based antacids are less effective, and antihistamines are slowly effective). Haenisch found a 44% increase in dementia for subjects taking proton pump inhibitors (PPIs), compared with subjects not taking them. However, patients taking a PPI for upper GI acid symptoms are more likely than are controls to have taken aluminum-based antacids (such as Maalox, Mylanta, Rolaids and many others). In the USA, physicians routinely inquire about the use of such antacids by patients suspected of having upper GI acid disorders.

Subjects taking PPIs logically must therefore be more likely to have a history of chronic aluminum exposure due to OTC antacid use than controls, and the 71% higher risk of dementia from their aluminum exposure is greater than the 44% increase found by Haenisch in association with PPI use. Attribution of increased risk for dementia to PPI use therefore requires correction of her dataset for exposure to aluminum antacids.

Haenisch stated "we were not able to include aluminum-containing antacids as these drugs are often not covered by the statutory health insurance in Germany". That was not how I learned epidemiology should be practiced, from a German epidemiology professor who goes out in work boots to collect the data herself if it is missing.

Therefore, the recommendation by Haenisch to avoid PPI use seems premature and should be withdrawn, as a public safety measure, until someone can truly address the following question: how much of the risk associated with PPI use is likely to be attributable to the use of aluminum-based antacids? Otherwise, we may witness an upsurge in peptic ulcer disease as patients and physicians prematurely embrace Haenisch' conclusions.

References

1: Keller DL. Proton Pump Inhibitors and Dementia Incidence. JAMA Neurol. 2016 Jun 20. doi: 10.1001/jamaneurol.2016.1488. [Epub ahead of print] PubMed PMID:27323287.

2: Wang Z, Wei X, Yang J, Suo J, Chen J, Liu X, Zhao X. Chronic exposure to aluminum and risk of Alzheimer's disease: A meta-analysis. Neurosci Lett. 2016 Jan 1;610:200-6. doi:10.1016/j.neulet.2015.11.014. Epub 2015 Nov 27. PubMed PMID: 26592479.

On 2016 Aug 07, David Keller commented:

Dementia caused by elevated aluminum levels in dialysis is not Alzheimer's disease: a distinction without a difference

Professor Haenisch gave two references to substantiate her statement that "the involvement of aluminum in the etiology of dementia seems to be a matter of debate". Immediately below, I summarize what I have learned from her first reference [1]:

Lidsky points out that the clinical presentation of dementia caused by elevated aluminum levels in dialysis patients is clearly distinct from that of true Alzheimer-type dementia. He also debunks the rumor that elevated aluminum levels cause the neurofibrillary tangles in the human brain which are pathognomonic for Alzheimer disease, noting that the neurofibrillary tangles caused by aluminum exhibit a distinctly different pattern when examined carefully under immunofluorescence, proving once and for all that the form of brain damage caused by aluminum is definitely not Alzheimer disease.

These findings are noted, but are of little comfort if they merely imply that aluminum ingestion causes brain damage and dementia which cannot be classified as Alzheimer type. As a primary-care physician who must answer patients' questions about the risks of dietary aluminum, that distinction truly makes no difference to patients or to myself.

Reference

[1] Lidsky TI. Is the aluminum hypothesis dead? J Occup Environ Med. 2014;56(5)(suppl): S73-S79.