High Degree of Heterogeneity in Alzheimer's Disease Progression Patterns

There have been several reports on the varying rates of progression among Alzheimer's Disease (AD) patients; however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow-up time of 4.78 years. Calculations for GDS/FAST stages 4–6 reveal that the standard deviations for stage durations are comparable with their mean values, indicating the presence of large variations in the AD progression among patients. Such amount of heterogeneity in the course of progression of AD is consistent with the existence of several sub-groups of AD patients, which differ by their patterns of decline.

[1]  C. Marra,et al.  Predictors of Cognitive Decline in the Early Stage of Probable Alzheimer’s Disease , 2000, Dementia and Geriatric Cognitive Disorders.

[2]  R. Brookmeyer,et al.  Survival following a diagnosis of Alzheimer disease. , 2002, Archives of neurology.

[3]  W. M. van der Flier,et al.  EEG Abnormalities Are Associated with Different Cognitive Profiles in Alzheimer’s Disease , 2010, Dementia and Geriatric Cognitive Disorders.

[4]  J. Growdon,et al.  Rate of progression of Alzheimer's disease is associated with genetic risk. , 1995, Archives of neurology.

[5]  B. Reisberg,et al.  Brief Cognitive Rating Scale (BCRS). , 1988, Psychopharmacology bulletin.

[6]  R. Green,et al.  Vascular factors predict rate of progression in Alzheimer disease , 2007, Neurology.

[7]  A. Heyman,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1993, Neurology.

[8]  B. Reisberg,et al.  Mortality and Temporal Course of Probable Alzheimer's Disease: A 5-Year Prospective Study , 1996, International Psychogeriatrics.

[9]  J Philip Miller,et al.  Rates of progression in mild cognitive impairment and early Alzheimer’s disease , 2002, Neurology.

[10]  B. Reisberg,et al.  The GDS/FAST Staging System , 1997, International Psychogeriatrics.

[11]  C. Jack,et al.  Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD , 2004, Neurology.

[12]  Donald Hedeker,et al.  Longitudinal Data Analysis , 2006 .

[13]  M. Weiner,et al.  Vascular Disease and Risk Factors, Rate of Progression, and Survival in Alzheimer’s Disease , 2006, Journal of geriatric psychiatry and neurology.

[14]  B. Reisberg,et al.  Functional Assessment Staging (FAST) in Alzheimer's Disease: Reliability, Validity, and Ordinality , 1992, International Psychogeriatrics.

[15]  W. M. van der Flier,et al.  CSF biomarkers in relationship to cognitive profiles in Alzheimer disease , 2009, Neurology.

[16]  W. M. van der Flier,et al.  CSF biomarkers predict rate of cognitive decline in Alzheimer disease , 2009, Neurology.

[17]  B. Turnbull.  The Empirical Distribution Function with Arbitrarily Grouped, Censored, and Truncated Data , 1976 .

[18]  J. Haxby,et al.  NIH conference. Alzheimer disease: clinical and biological heterogeneity. , 1988, Annals of internal medicine.

[19]  F. Chiappelli,et al.  Physiologic modulation of natural killer cell activity as an index of Alzheimer's disease progression , 2007, Bioinformation.

[20]  Wenyaw Chan,et al.  Predicting progression of Alzheimer's disease , 2010, Alzheimer's Research & Therapy.

[21]  J. Morris,et al.  Aphasia, family history, and the longitudinal course of senile dementia of the alzheimer type , 1985, Psychiatry Research.

[22]  S. Lagakos,et al.  Estimation of the infection time and latency distribution of AIDS with doubly censored data. , 1994, Biometrics.

[23]  R. Mayeux,et al.  Heterogeneity in dementia of the Alzheimer type , 1985, Neurology.

[24]  J. Touchon,et al.  Heterogeneity in senile dementia of the Alzheimer type: individual differences, progressive deterioration or clinical sub-types? , 1992, Journal of clinical epidemiology.

[25]  J. Yesavage,et al.  Rate of cognitive decline in AD is accelerated by the interleukin-1α −889 *1 allele , 2001, Neurology.

[26]  Steven D. Edland,et al.  Accelerated decline in apolipoprotein E-ϵ4 homozygotes with Alzheimer's disease , 1998, Neurology.

[27]  Nick C Fox,et al.  Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study , 2006, The Lancet Neurology.

[28]  B. Reisberg,et al.  Dementia: a systematic approach to identifying reversible causes. , 1986, Geriatrics.

[29]  J. Singer,et al.  Applied Longitudinal Data Analysis , 2003 .

[30]  B. Reisberg,et al.  The Global Deterioration Scale for assessment of primary degenerative dementia. , 1982, The American journal of psychiatry.

[31]  S W Lagakos,et al.  Analysis of doubly-censored survival data, with application to AIDS. , 1989, Biometrics.

[32]  Nick C Fox,et al.  Whole-brain atrophy rate in Alzheimer disease , 2008, Neurology.

[33]  Salem Sn.  RECURRENT CEREBRAL ISCHAEMIA. , 1964 .

[34]  Geert Molenberghs,et al.  A review on linear mixed models for longitudinal data, possibly subject to dropout , 2001 .

[35]  R. Bartha,et al.  Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database. , 2008, Brain : a journal of neurology.

[36]  Guk-Hee Suh,et al.  A longitudinal study of Alzheimer's disease: rates of cognitive and functional decline , 2004, International journal of geriatric psychiatry.

[37]  Craig J. Thalhauser,et al.  Alzheimer's disease: rapid and slow progression , 2012, Journal of The Royal Society Interface.

[38]  E B Larson,et al.  Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease. , 1998, Neurology.

[39]  E. Mohr,et al.  RAPIDLY PROGRESSIVE ALZHEIMER'S DISEASE , 1989, The Lancet.

[40]  G. Molenberghs,et al.  Longitudinal data analysis , 2008 .

[41]  A. Dale,et al.  Alzheimer disease: quantitative structural neuroimaging for detection and prediction of clinical and structural changes in mild cognitive impairment. , 2009, Radiology.

[42]  B. Reisberg.  Functional assessment staging (FAST). , 1988, Psychopharmacology bulletin.

[43]  B. Reisberg,et al.  Functional, global and cognitive decline correlates to accumulation of Alzheimer's pathology in MCI and AD. , 2010, Current Alzheimer research.

[44]  P. Rabins.  Predicting progression of Alzheimer disease. , 1997, Journal of the American Medical Association (JAMA).

[45]  E. Mohr,et al.  Heterogeneity in Alzheimer's disease: progression rate segregated by distinct neuropsychological and cerebral metabolic profiles. , 1992, Journal of neurology, neurosurgery, and psychiatry.

[46]  A. Fagan,et al.  SNPs Associated with Cerebrospinal Fluid Phospho-Tau Levels Influence Rate of Decline in Alzheimer's Disease , 2010, PLoS genetics.