Age and Rate of Cognitive Decline in Alzheimer Disease: Implications for Clinical Trials
Abstract
BACKGROUND: Factors that affect the rate of progression of Alzheimer disease (AD) need to be considered in the clinical trial designs of potential disease-modifying therapies. OBJECTIVE: To determine the influence of age on AD course in a clinical trial setting. DESIGN: Pooled cohort study from 3 AD clinical trials of 18-month duration conducted by the Alzheimer Disease Cooperative Study group. SETTING: Alzheimer disease research centers from across the United States. PATIENTS: Four hundred seventy-one subjects with mild to moderate AD assigned to the placebo arm of 3 clinical trials. MAIN OUTCOME MEASURES: The relationships between baseline age and rate of change in the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog) 11, Mini-Mental State Examination, Clinical Dementia Rating scale Sum of Boxes score, Alzheimer Disease Cooperative Study–activities of daily living scale, and Neuropsychiatric Inventory were analyzed using a mixed-effect regression model. Sample size calculation for possible future AD clinical trials lasting 18 months using the results of the change in ADAS-cog 11 by tertiles of age groups. RESULTS: Older age at baseline was associated with a slower rate of decline in the ADAS-cog 11 and the Mini-Mental State Examination scores. Almost twice as many subjects aged 80 years and older compared with those aged younger than 70 years would be required to demonstrate a 30% treatment effect on the ADAS-cog 11 in an 18-month AD trial. CONCLUSION: Subject age is an important factor to consider when defining the study population in and analyzing data from AD trials of potential disease-modifying therapies.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Composite scores encompassing multiple neuropsychological tests can provide some of the most reliable assessments of global cognitive status relating to AD and serve as efficacy outcome measures in clinical trials.
“Composite scores encompassing multiple neuropsychological tests are often used and can provide some of the most reliable assessments of global cognitive status relating to AD as well as serving as efficacy outcome measures in clinical trials (Bernick et al., 2012).”
From Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models (2014) · cites this paper as Bernick et al., 2012
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
A new rating scale for Alzheimer's disease
(1984) · American Journal of Psychiatry · doi:10.1176/ajp.141.11.1356 · Cited by 4,175 · see citing works
Morris, J. C. (1997) · International Psychogeriatrics · doi:10.1017/s1041610297004870 · Cited by 1,641 · see citing works
Alzheimer’s Disease Neuroimaging Initiative
Mueller, S. G., Weiner, M. W., Thal, L. J., Petersen, R. C., Jack, C. R., Jagust, W. J., Trojanowski, J. Q., Toga, A. W., & Beckett, L. A. (2007) · Springer eBooks · doi:10.1007/978-0-387-72076-0_18 · Cited by 1,493 · see citing works
An Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimerʼs Disease
Galasko, D., Bennett, D. A., Sano, M., Ernesto, C., Thomas, R., Grundman, M., & Ferris, S. H. (1997) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-199700112-00005 · Cited by 1,198 · see citing works
Murray, M. E., Graff-Radford, N. R., Ross, O. A., Petersen, R. C., Duara, R., & Dickson, D. W. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70156-9 · Cited by 972 · see citing works
Individual differences in rates of change in cognitive abilities of older persons.
Wilson, R. S., Beckett, L. A., Barnes, L. L., Schneider, J. A., Bach, J., Evans, D. A., & Bennett, D. A. (2002) · Psychology and Aging · doi:10.1037/0882-7974.17.2.179 · Cited by 842 · see citing works
Galasko, D. R., Bennett, D., Sano, M., Ernesto, C., Thomas, R., Grundman, M., & Ferris, S. H. (1997) · PubMed · Cited by 767 · see citing works
The topography of grey matter involvement in early and late onset Alzheimer's disease
Frisoni, G. B., Pievani, M., Testa, C., Sabattoli, F., Bresciani, L. C., Bonetti, M., Beltramello, A., Hayashi, K. M., Toga, A. W., & Thompson, P. M. (2007) · Brain · doi:10.1093/brain/awl377 · Cited by 433 · see citing works
(1994) · American Journal of Psychiatry · doi:10.1176/ajp.151.3.390 · Cited by 408 · see citing works
A Comparison of Clinical Features in Early- and Late-Onset Primary Degenerative Dementia
Seltzer, B. (1983) · Archives of Neurology · doi:10.1001/archneur.1983.04050030037006 · Cited by 365 · see citing works
Longitudinal MRI atrophy biomarkers: Relationship to conversion in the ADNI cohort
Risacher, S. L., Shen, L., West, J. D., Kim, S., McDonald, B. C., Beckett, L. A., Harvey, D. J., Jack, C. R., Weiner, M. W., & Saykin, A. J. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.04.029 · Cited by 276 · see citing works
Jacobs, D., Sano, M., Marder, K., Bell, K., Bylsma, F., Lafleche, G., Albert, M., Brandt, J., & Stern, Y. (1994) · Neurology · doi:10.1212/wnl.44.7.1215 · Cited by 266 · see citing works
Sex and age differences in atrophic rates: an ADNI study with n=1368 MRI scans
Hua, X., Hibar, D. P., Lee, S., Toga, A. W., Jack, C. R., Weiner, M. W., & Thompson, P. M. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.04.033 · Cited by 234 · see citing works
β‐amyloid burden is not associated with rates of brain atrophy
Josephs, K. A., Whitwell, J. L., Ahmed, Z., Shiung, M. M., Weigand, S. D., Knopman, D. S., Boeve, B. F., Parisi, J. E., Petersen, R. C., Dickson, D. W., et al. (2007) · Annals of Neurology · doi:10.1002/ana.21223 · Cited by 224 · see citing works
Leow, A. D., Yanovsky, I., Parikshak, N., Hua, X., Lee, S., Toga, A. W., Jack, C. R., Bernstein, M. A., Britson, P. J., Gunter, J. L., et al. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.01.004 · Cited by 180 · see citing works
Disease-modifying trials in Alzheimer's disease: a European task force consensus.
Vellas, B., Andrieu, S., Sampaio, C., & Wilcock, G. (2007) · Lancet Neurology · doi:10.1016/s1474-4422(06)70677-9 · Cited by 154 · see citing works
Current Alzheimer's disease clinical trials: Methods and placebo outcomes
Schneider, L. S. S., & Sano, M. C. (2009) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2009.07.038 · Cited by 137 · see citing works
Change in Cognitive Function in Older Persons From a Community Population
Wilson, R. S., Beckett, L. A., Bennett, D. A., Albert, M., & Evans, D. A. (1999) · Archives of Neurology · doi:10.1001/archneur.56.10.1274 · Cited by 133 · see citing works
Education and the course of cognitive decline in Alzheimer disease
Wilson, R. S., Li, Y., Aggarwal, N. T., Barnes, L. L., McCann, J. J., Gilley, D. W., & Evans, D. A. (2004) · Neurology · doi:10.1212/01.wnl.0000140488.65299.53 · Cited by 133 · see citing works
Whole-brain atrophy rate in Alzheimer disease: Identifying fast progressors
Sluimer, J. D., Vrenken, H., Blankenstein, M. A., Fox, N. C., Scheltens, P., Barkhof, F., & van der Flier, W. M. (2008) · Neurology · doi:10.1212/01.wnl.0000311446.61861.e3 · Cited by 110 · see citing works
Doraiswamy, P. M., Kaiser, L., Bieber, F., & Garman, R. L. (2001) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-200110000-00003 · Cited by 104 · see citing works
Mungas, D., Reed, B. R., Ellis, W. G., & Jagust, W. J. (2001) · Archives of Neurology · doi:10.1001/archneur.58.8.1243 · Cited by 104 · see citing works
Age at onset is associated with disease severity in Lewy body variant and Alzheimer's disease
Ho, G., Hansen, L., Alford, M., Foster, K., Salmon, D., Galasko, D., Thal, L., & Masliah, E. (2002) · NeuroReport · doi:10.1097/00001756-200210070-00028 · Cited by 69 · see citing works
Neurotransmitter changes in early- and late-onset alzheimer-type dementia
Heii, A., Ichimiya, Y., Kenji, K., Takashi, M., & Iizuka, R. (1992) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/0278-5846(92)90106-o · Cited by 42 · see citing works
Relationship of Amyloid-Beta Burden With Age-At-Onset in Alzheimer Disease
Choo, I. H., Lee, D. Y., Kim, J. W., Seo, E. H., Lee, D. S., Kim, Y. K., Kim, S. G., Park, S. Y., Woo, J. I., & Yoon, E. J. (2010) · American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e318202bf3a · Cited by 34 · see citing works
Assessing Outcomes in Alzheimer Disease
Schneider, L. S. (2001) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-200108001-00003 · Cited by 31 · see citing works
Irizarry, M. C., Webb, D. J., Bains, C., Barrett, S. J., Lai, R. Y. K., Laroche, J. P., Hosford, D. A., Maher‐Edwards, G., & Weil, J. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-14304 · Cited by 30 · see citing works
Gold, M. (2007) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v68n0313 · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Webster, S. J., Bachstetter, A. D., Nelson, P. T., Schmitt, F. A., & Van Eldik, L. J. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00088 · Cited by 755 · see citing works
“Composite scores encompassing multiple neuropsychological tests are often used and can provide some of the most reliable assessments of global cognitive status relating to AD as well as serving as efficacy outcome measures in clinical trials (Bernick et al., 2012).”
BackgroundShaw, L. M., Arias, J., Blennow, K., Galasko, D., Molinuevo, J. L., Salloway, S., Schindler, S., Carrillo, M. C., Hendrix, J. A., Ross, A., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.07.220 · Cited by 266 · see citing works
Higher Rates of Decline for Women and <i>Apolipoprotein E</i> ε4 Carriers
Holland, D., Desikan, R. S., Dale, A. M., & McEvoy, L. K. (2013) · American Journal of Neuroradiology · doi:10.3174/ajnr.a3601 · Cited by 219 · see citing works
- Authors
- Bernick, C., Cummings, J., Raman, R., Sun, X., & Aisen, P.
- Affiliations
- Cleveland Clinic (US)
- Lou Ruvo Brain Institute (US)
- University of California San Diego (US)
- Corresponding author
- Bernick, Charles
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2012-07-01
- Volume
- 69
- Issue
- 7
- Pages
- 901-5
- ISSN
- 0003-9942 (ISSN-L)
- OpenAlex
- W2049722644
- Cited by
- 85
- References
- 29
- Citations by year
- 2026: 7 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 9 · 2021: 6 · 2020: 2 · 2019: 7 · 2018: 7 · 2017: 7 · 2016: 6 · 2015: 9 · 2014: 7 · 2013: 6 · 2012: 3
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- Alzheimer's disease, age effects, disease-modifying therapy, clinical trial design, sample size determination, Mini-Mental State Examination, Clinical Dementia Rating, activities of daily living, neuropsychiatric symptoms, older adults
- MeSH terms
- Activities of Daily Living, Age Factors, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Cognition Disorders, Female, Humans, Male, Neuropsychological Tests, Psychiatric Status Rating Scales, Antipsychotic Agents, United States, Cohort Studies, Multicenter Studies as Topic, Outcome Assessment, Health Care, Clinical Trials, Phase III as Topic
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
