Summer School on Neuroscience & Aging Venice, 10 - 15 June 2013 Prevention of the dementing disorders: from observation to intervention Laura Fratiglioni www.ki-su-arc.se

Outline Part I (30 min +10 for discussion) Methodological issues: clinical and epidemiological A model for dementia development Part II (30 min +10 for discussion) 3. Risk factors 4. Protective factors 5. Summary-current knowledge Part III (20 min +10 for discussion) 6. Future perspectives 31 December 2018 Laura Fratiglioni

METHODOLICAL ISSUES IN THE EPIDEMIOLOGY OF DEMENTIA PART I METHODOLICAL ISSUES IN THE EPIDEMIOLOGY OF DEMENTIA PROTECTING THE HUMAN BRAIN AND REDUCING THE RISK OF DEMENTIA Laura Fratiglioni Laura Fratiglioni www.ki-su-arc.se

Epidemiology of Dementia & AD: Topics Descriptive epidemiology Etiological epidemiology Clinical epidemiology Occurrence Public health Etiology Risk factors Diagnosis Markers Prognosis Natural history Laura Fratiglioni 31 December 2018 3

Dementia: challenging issues Disease of the older people Diagnostic validity Underreport in official statistics Hospitalization for selected cases Slow and insidious onset Presence of co-morbidity Multifactorial Lifespan risk Laura Fratiglioni 31 December 2018 3

Disease of the older people Laura Fratiglioni 31 December 2018 3

Disease of the older people Drop-outs due weakness and disease Attrition both at baseline and follow-up Misclassification of the exposure, especially in case control studies - recall bias - unbalance exposure assessment Competing risk of death Laura Fratiglioni 31 December 2018 3

The Kungsholmen Project Baseline 1st follow-up 2nd follow-up 3rd follow-up 4th follow-up 1987-1989 1991-1993 1994-1996 1997-1998 1999-2000 1

The Kungsholmen Project 1810 Participants 23.6% Drop-outs 1099 Participants 24% Deceased 15.5% Drop-outs 680 Participants 33% Deceased 5% Drop-outs 421 Participants 32% Deceased 6% Drop-outs 265 Participants 30% Deceased 7% Drop-outs 1987-89 1991-93 1994-96 1997-98 1999-2000 Baseline 1st Follow-up 2nd Follow-up 3rd Follow-up 4th Follow-up 1

Dementia: challenging issues Disease of the older people Diagnostic validity Underreport in official statistics Hospitalization for selected cases Slow and insidious onset Presence of co-morbidity Multifactorial Lifespan risk Laura Fratiglioni 31 December 2018 3

Diagnostic validity No biological markers Variability Missing mild/early cases Selection bias Misclassification of the outcome decreased power bias Laura Fratiglioni 31 December 2018 3

Rethinking the classification of degenerative and vascular cases One challenge is the overlapping between AD and VaD. 55% mixed; AD with vascular involvment or VaD with AD type of course. 75+ Viswanathan, Rocca, Tzourio, Neurology, May 2009 Kalaria R et al. Alzheimer Dis Assoc Disord 1999 Aguero-Torres et al, 2001 12 12

Distribution of dementia subtypes: incident cases MIXED DEMENTIA Longitudinal studies on dementia in Europe (Fratiglioni et al, Neurology 2000) Distribution of dementia subtypes: incident cases MIXED CASES Aguero-Torres, 2001

Neuropathology of Alzheimer Disease and MCI Schneider et al Ann Neurol 2009 Mixed dementia

Age, Neuropathology, and Dementia Savva et al, NEJM 2009 Mixed dementia

Dementia: challenging issues Disease of the older people Diagnostic validity Underreport in official statistics Hospitalization for selected cases Slow and insidious onset Presence of co-morbidity Multifactorial Lifespan risk Laura Fratiglioni 31 December 2018 3

Underreport in official statistics Population IPR + CDR Prevalent cases KP 50.2 (47.7-52.8) Incident cases KP 47.9 (45.3-50.6) Prev. cases SNAC-K 42.1 (40.3-43.9) Laura Fratiglioni 31 December 2018 3

Dementia: challenging aspects Underreport in official statistics Hospitalization for selected cases Selection bias Misclassification of the outcome decreased power bias Laura Fratiglioni 31 December 2018 3

Dementia: challenging issues Disease of the older people Diagnostic validity Underreport in official statistics Hospitalization for selected cases Slow and insidious onset Presence of co-morbidity Multifactorial Lifespan risk Laura Fratiglioni 31 December 2018 3

CIND

Social network and AD STUDY POPULATION Detection of incident cases Fratiglioni et al, Lancet 2000 STUDY POPULATION Detection of incident cases Assessment of social network 1203 non-demented persons 176 demented subjects Baseline 1987 - 1989 1st follow-up 1991 - 1993

Leisure activities & dementia Wang et al, Am J Epidemiol 2002 STUDY POPULATION Assessment of engagement in leisure activities Detection of incident cases 776 non demented 123 demented Baseline 1987 - 1989 1st follow-up 1991-1993 2nd follow-up 1994 - 1996

Dementia: challenging aspects Slow and insidious onset Precipitating rather than risk factors Reverse causality Laura Fratiglioni 31 December 2018 3

Dementia: challenging issues Disease of the older people Diagnostic validity Underreport in official statistics Hospitalization for selected cases Slow and insidious onset Presence of co-morbidity Multifactorial Lifespan risk Laura Fratiglioni 31 December 2018 3

54.8% Multimorbidity (2+ diseases) Most common chronic disorders among 75+ old people Multimorbidity (2+ diseases)   54.8% (50.8-58.8) Marengoni et al, Am J Publ Health 2008

Age-specific prevalence per 100 for number of chronic diseases No diseases %

Dementia: challenging issues Disease of the older people Diagnostic validity Underreport in official statistics Hospitalization for selected cases Slow and insidious onset Presence of co-morbidity Multifactorial Lifespan risk Laura Fratiglioni 31 December 2018 3

Brain Reserve Capacity Risk Factors: biological & contextual Vascular mechanisms Neuro- degeneration Toxicity Oxidative stress Inflammation Genetic background Birth Childhood- Adult life- Older 2nd decade Middle age Transition age Brain lesions 20 60 75 Brain Reserve Capacity Psychosocial factors Nutrition Protective Factors

Dementia: challenging aspects Disease of the older people Questionable diagnostic validity Underreport in official statistics Hospitalization for selected cases Slow and insidious onset Presence of co-morbidity Multifactorial Life span Life time cumulative exposure Exposure windows Laura Fratiglioni 31 December 2018 3

Dementia: challenging aspects Disease of the older people Questionable diagnostic validity Underreport in official statistics Hospitalization for selected cases Slow and insidious onset Presence of co-morbidity Multifactorial Lifespan risk Study population Study design Drop-outs Case detection Diagnosis Exposure Confounders Bias Power Temporal relation 3

Epidemiological evidence in dementia SBU 2005 Wang & Fratiglioni JAD 2007 Internal validity index 4 grades (not-acceptable; low, medium; high) 9 items (Population types, Design,Drop-outs, Case detection, Diagnosis,Exposure, Confounders, Bias, Power) Causal criteria index 4 grades (not-acceptable; low, medium; high) 3 items (Strength, Temporality, Biolog. gradient)

Epidemiological evidence in dementia Grading the evidence Quantity Low Medium High Insufficient Limited Moderate Substantial Strong Final quality index

Questions