- Alzheimer's disease (AD) is the most common cause of dementia. The hallmark features are amyloid plaques and neurofibrillary tangles in the brain. - AD pathology begins decades before symptoms appear. Biomarkers show amyloid deposition may start 25 years before diagnosis, with cognitive impairment appearing around 5 years prior. - Genetic risk factors include mutations linked to early-onset AD as well as the APOE ε4 allele associated with late-onset disease. Having a family history or experiencing head trauma also increases risk. - Acquired risk factors like midlife hypertension, obesity, diabetes, or physical inactivity are associated with increased AD risk later in life. Cerebrovascular disease frequently

1. ALZHEIMERS DEMENTIA-
PATHOLOGY AND
PATHOPHYSIOLOGY

2. • Alzheimer disease is the most common cause of dementia and one of
the leading sources of morbidity and mortality in the aging population.
• The hallmark neuropathologic changes of AD are diffuse and neuritic
plaques, marked by extracellular amyloid beta deposition, and
neurofibrillary tangles, comprised of the intracellular accumulation of
hyperphosphorylated tau (p-tau) protein.

3. • The study of AD has focused on three interrelated hypotheses :
• Extracellular amyloid plaques primarily composed of amyloid beta
peptides are a unique genetic and lifestyle disease  increased
production of amyloid beta in younger, genetically high-risk individuals and
reduced metabolism and removal among older individuals.
• Vascular disease is an independent determinant of vascular dementia
but also of increased amyloid deposition and neurodegeneration.

4. • Dementia in older individuals is a syndrome that derives most
commonly from an individually varying mixture of diseases that afflict
the brain.
• The most prevalent of these is AD, but it commonly occurs along with
other diseases of the brain, vascular brain injury, Lewy body disease, and
hippocampal sclerosis (HS).

5. PATHOLOGY
Essential neuropathologic changes of AD include the following:
• Extracellular deposits of amyloid beta peptides
• Neuritic plaques, associated with neuronal injury and characterized by
amyloid formed from amyloid beta with dystrophic neurites that
frequently have phospho-tau immunoreactivity

6. • Neurofibrillary degeneration, best exemplified by neurofibrillary
tangles
• AD neuropathologic change is ranked along three parameters:
amyloid beta plaque distribution score , neurofibrillary tangle
distribution stage, and neuritic plaque density score .
• An overall assessment of low, intermediate, or high levels of AD
neuropathologic change is obtained based on these three parameters.

7. • Cerebral amyloid angiopathy is often found in cases with parenchymal
amyloid beta deposits .
• Inclusions of abnormal alpha-synuclein accumulation, known as Lewy
bodies, are common in the setting of intermediate-to-high levels of AD
neuropathologic change, including some early-onset familial AD cases .
• Lewy bodies in AD often include extensive deposition in the amygdala.

8. • Vascular brain injury is encountered commonly in brains with AD.
• Pathologic changes of vascular brain injury are caused by oligemia,
hypoxemia, or ischemia involving different caliber vessels in different
regions of brain.

9. • Hippocampal sclerosis (HS) in AD is defined by pyramidal cell loss and
gliosis in the hippocampal formation that is out of proportion to AD
neuropathologic change .
• HS can be observed alone or in the context of AD, frontotemporal
lobar degeneration, or vascular brain injury

10. • Immunoreactive inclusions of TAR DNA binding protein 43 (TDP-43)are
also commonly observed in cases with AD neuropathologic change
• Hippocampal TDP-43 deposition is associated with faster clinical
progression and hippocampal atrophy among patients with AD

11. PATHOGENESIS
• While the pathogenesis of AD remains unclear, all forms of AD appear
to share overproduction and/or decreased clearance of amyloid beta
peptides.
• Amyloid beta peptides are produced by the endoproteolytic cleavage
of mature protein translated from the amyloid beta precursor protein
(APP) gene and cleaved by beta-secretase and gamma-secretase.

12. • Presenilin forms part of the gamma-secretase complex, and mutations
in presenilin 1 (PSEN1) or presenilin 2 (PSEN2) appear to favor
production of amyloid beta overall, or more neurotoxic forms of amyloid
beta.
• The ultimate neurotoxin in AD is debated, but experimental evidence
highlights small aggregates of amyloid beta peptides called oligomers, as
opposed to larger aggregates called fibrils

14. • The pathogenesis of AD also involves a second protein, tau.
• Tau is a microtubule-associated protein that aids in microtubule
assembly and stabilization.
• In AD, tau becomes hyperphosphorylated and aggregates to form
paired helical filament (PHF) tau, a major component of neurofibrillary
tangles within the neuronal cytoplasm.

15. • The accumulation of this altered protein is toxic to neurons
• Transmission of pathologic forms of tau between neurons has been
proposed to account for the spread of AD in the brain, which follows a
distinct progression across brain regions as AD advances
• There are several other important and potentially overlapping
pathways likely involved in AD pathogenesis

16. • The human apolipoprotein E (APOE) gene is a pleiotropic lipoprotein
involved in multiple cellular processes including cholesterol transport,
development, synaptic plasticity, and immune regulation, among others.
• There are three alleles of APOE, called epsilon 2 (e2), e3, and e4, and
their encoded isoforms also vary in several activities.
• At least one mechanism by which inheritance of APOE e4 may increase
AD risk is impairment of amyloid beta clearance from cerebrum

17. CASE DEFINITION
• A definitive diagnosis of AD requires histopathologic examination, but
most studies of AD rely on clinical criteria to define cases.

18. PRESYMPTOMATIC PERIOD
• There is a long presymptomatic period between the onset of
pathophysiologic processes in the brain and the development of clinical
symptoms of AD
• In the Rotterdam Study, the average age at diagnosis of dementia was
82 years, and memory complaints in these patients began 16 years
before diagnosis .

19. • The long presymptomatic period has been demonstrated in
families with dominantly inherited AD due to genetic mutations in
amyloid beta precursor protein (APP), presenilin 1 (PSEN1), or presenilin
2 (PSEN2) .
• Such mutations carry a nearly 100 percent risk of early-onset AD,
which is typically diagnosed between 35 and 50 years of age,
depending on the family.

20. • Parental age at onset of AD in the index cases was used to estimate the
relationship between disease biomarkers and the onset of clinical AD.
• A decline in amyloid beta 1 through 42 in cerebrospinal fluid (CSF)
appeared to precede disease onset by 25 years

21. • Amyloid in the brain measured by Pittsburgh compound-B (PiB)
retention on positron emission tomography (PET) scan, phospho-tau in
CSF, and magnetic resonance imaging (MRI) measures of brain atrophy
appear to be present approximately 15 years prior to onset of disease.
• Measurable cognitive impairment appears to occur approximately five
years prior to clinical diagnosis.

22. • These biomarkers appear to identify a presymptomatic period for AD in
the general population as well.
• Neuroimaging findings including amyloid positivity on PET, as well as
white matter lesions, neurodegeneration (cortical thickness), and small
hippocampal volumes measured on MRI, have been found to be
associated with cognitive decline and incident dementia, particularly
when these findings occur in combination

24. GENETIC RISK FACTORS
• Aside from age, the most clearly established risk factors for AD are a
family history of dementia, rare dominantly inherited mutations in genes
that impact amyloid in the brain, and the apolipoprotein E (APOE)
epsilon 4 (e4) allele.

25. EARLY-ONSET ALZHEIMER DISEASE
• The genetic basis for AD is understood most clearly in the early-onset
form, which accounts for less than 1 percent of cases.
• Early-onset AD follows an autosomal dominant inheritance pattern
related to mutations in genes that alter amyloid beta protein
production, aggregation, or clearance, including amyloid beta precursor
protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2).
• Such mutations are highly penetrant,carriers have a nearly 100 percent
chance of developing the disease in their lifetime.

26. • Other early-onset cases without mutations can present clinically prior
to 65 years of age.
• While these individuals have higher than expected inheritance of APOE
e4, not all do, and this early-onset group is not fully understood

27. LATE-ONSET ALZHEIMER DISEASE
The genetic basis of late-onset AD is more complex, with susceptibility
likely conferred by a variety of more common but less penetrant genetic
factors interacting with environmental and epigenetic influences.
The most firmly established genetic risk factor for late-onset AD is APOE

28. • Carriers of one e4 allele are at two- to threefold increased odds of
developing AD compared with noncarriers, and those with two e4 alleles
are at approximately 8- to 12-fold increased odds.
• The strength of the association may be modified by several factors,
including sex, race, and vascular risk factors.

29. FAMILY HISTORY
Family history of dementia is a risk factor for the development of AD;
patients with a first-degree relative with dementia have a 10 to 30
percent increased risk of developing the disorder .
Individuals in families with two or more affected siblings with late-onset
AD have a threefold increased risk of AD compared with the general
population

30. • First-degree relatives of African Americans with AD appear to have a
higher cumulative risk of dementia than relatives of White Americans.
• The cumulative risk of the disorder in the African American and White
relatives was 43.7 and 26.9 percent, respectively

31. ACQUIRED RISK FACTORS
• A variety of polygenic or acquired factors influence risk for dementia
and perhaps specifically the risk for AD, including hypertension,
dyslipidemia, cerebrovascular disease, altered glucose metabolism, and
brain trauma.
• Many of these risk factors appear to be most relevant when they are
present in midlife .

32. • Individuals with two or more vascular risk factors in midlife had nearly
threefold higher odds of brain amyloid deposition in late life as measured
by amyloid positron emission tomography (PET)
• Aggressive management of vascular risk factors during midlife
represents a key strategy for reducing risk, progression, and severity of
AD and other forms of dementia

33. • It has been estimated that up to one-third of AD cases worldwide
might be attributable to modifiable risk factors such as diabetes, midlife
hypertension, and physical inactivity

34. HYPERTENSION
• Midlife hypertension has been consistently associated with risk of
dementia and AD in cross-sectional and longitudinal cohort studies .
• The risk is probably mediated through cerebrovascular disease and
the long-term effects of elevated blood pressure, smoking, and
diabetes
• The association may be stronger in females than males, although this
finding has not been consistent .

35. • Arteriolosclerosis and blood pressure variability may play an important
role in the relationship between blood pressure and the risk of AD .
• Cerebral arteriolosclerosis increases with age, blood pressure levels,
and possibly diabetes and smoking .

36. • In a cohort of dementia-free older adults ages 83 to 96 years, for
example, arterial stiffness was directly related to amyloid beta plaque
deposition, independent of blood pressure and apolipoprotein E (APOE)
genotype
• Long-term treatment of hypertension, particularly beginning in
midlife, alters AD risk later in life

37. DYSLIPIDEMIA
• Peripheral blood LDL-C does not cross the blood-brain barrier unless
the barrier is damaged by factors such as vascular disease.
• Most of the cholesterol in the brain is synthesized by astrocytes and
neurons and provided to brain cells by high-density lipoprotein (HDL)
complexes, and there is little or no LDL-C in the brain
• High total cholesterol at midlife (mean age 50 years) conferred threefold
higher odds of AD, independent of APOE genotype, education level, smoking
status, and alcohol consumption

38. • When late-life cholesterol levels are examined, results have been
mixed, with some studies finding a positive association between
cholesterol and AD or dementia risk , and others finding either no
correlation or an inverse relationship.
• Elevated total cholesterol and LDL-C have also been associated with
higher rates of cognitive decline in patients with AD .

39. • Brain cholesterol may increase the risk of AD by enhancing the
formation and/or deposition of amyloid beta, or that it may affect
nonamyloid factors such as cerebrovascular risk, local inflammation, or
tau metabolism
• Oral statins also do not affect the rate of decline in mild to moderate
AD.

40. CEREBROVASCULAR DISEASE
Cerebrovascular disease and AD frequently coexist, and the co-
occurrence of AD pathologic changes and vascular brain injury is a
common form of mixed dementia.
Cerebral small vessel disease is common in aging, does not occur in
isolation, and is often comorbid with AD.
Risk factors include hypertension, diabetes, smoking, obesity, low
physical activity, and hyperlipidemia

41. • Decreased blood flow has been proposed to contribute directly to
amyloid accumulation, probably by impairment of clearance of amyloid.
• Vascular factors may also contribute to the breakdown of the blood-
brain barrier .
• Decreased cerebral blood flow (CBF) was associated with an increased
risk of AD, particularly in combination with white matter
abnormalities.

42. • The APOE epsilon 4 (e4) allele is associated with an increased risk of
cardiovascular disease and with AD.
• The severity of coronary artery disease was significantly associated
with the density of AD neuropathologic features, primarily in APOE e4
carriers
• APOE e4 was associated with subcortical microvascular changes but
not gross cerebrovascular pathology in patients with AD .

43. • Cerebrovascular disease has been associated with worse cognitive
performance in patients with AD
• Clinicopathologic studies suggest that cerebrovascular disease lowers
the threshold for clinical dementia in patients with a neuropathologic
diagnosis of AD .

44. • Increased risk of AD in association with various neuroimaging or
pathologic markers of cerebrovascular disease, including atherosclerosis
in the circle of Willis, periventricular white matter lesions,cerebral
microbleeds,and cortical infarcts.

45. PERIPHERAL AND CARDIOVASCULAR ATHEROSCLEROSIS
• Markers of peripheral atherosclerotic disease burden, including
measures of carotid intima media thickness and coronary artery
calcification, have also been associated with an increased risk of
dementia and AD.
• It is possible that such associations are modulated by arteriosclerosis
and vascular brain disease, especially white matter lesions and
microinfarcts in the brain

46. TYPE 2 DIABETES AND OBESITY
Obesity and type 2 diabetes have been associated with an
approximately 1.5-fold increased risk of AD.
The data are strongest for midlife obesity and more mixed for
late-life body mass index.
?direct effects of hyperinsulinemia and insulin resistance in the brain
? possible relationship between insulin and amyloid beta
metabolism, are areas of active investigation .

47. • Role of insulin-degrading enzyme (IDE), which metabolizes both
amyloid beta and insulin, in the accumulation of oligomeric beta
amyloid.
• Pathogenic role for the accumulation of advanced glycation end
products within brain tissue

48. LIFESTYLE AND ACTIVITY
Physically active individuals have lower incidence and prevalence of
cognitive decline and dementia, including AD .
A meta-analysis of 16 prospective studies suggested a 28 percent
reduction in overall dementia and a 45 percent reduction in AD among
those who were physically active compared with those who were less
active, even after adjusting for confounding variables

49. • The Alzheimer's Association and the World Dementia Council reviewed
the evidence for modifiable risk factors for cognitive decline and
dementia and concluded that sufficient evidence supports the link
between regular physical activity and management of cardiovascular
risk factors diabetes, obesity, smoking, and hypertension and reduced
risk of cognitive decline and possibly dementia.
They also found strong evidence to conclude that a healthy diet and
lifelong learning /cognitive training may also reduce the risk of cognitive
decline.

50. • Small clinical trials have also shown that exercise improves cognitive
function and may also increase hippocampal and total brain volume
• Most of these trials were of short duration, however, and no trials have
evaluated the effects of sustained exercise on the long-term risk of AD

51. BRAIN TRAUMA
History of severe brain trauma with loss of consciousness of 30 minutes
or more has been inconsistently associated with an increased risk of AD .
A causal relationship has been suggested by the finding of increased
amyloid in the brain shortly after severe brain trauma .
Repeated milder forms of head trauma have been associated with
neuropathologic changes of a tauopathy that is distinct from AD.

52. MEDICATIONS
• Multiple studies have found an association between use of certain
medication classes  benzodiazepines, anticholinergics, antihistamines,
opioids and cognitive impairment in older adults, but the effects have been
presumed to be transient and reversible
• Long-term exposure has been linked to an elevated risk of AD or all-
cause dementia in several large studies
• Possibility that cognitive effects may not be reversible in some patients
or that these exposures somehow enhance the penetrance of
presymptomatic AD.

53. Benzodiazepines
• Available data on the association between benzodiazepine use and
dementia risk are conflicting.
• A dose-response effect was observed, with longer exposure and longer
half-life drugs associated with increased risk.

54. • Anticholinergics – The case for anticholinergics increasing the risk of
irreversible effects is probably stronger and is plausible given the
prominence of cholinergic deficits in AD.
• Proton pump inhibitors – There are conflicting data on the association
between proton pump inhibitors (PPIs) and risk of AD.
• Malabsorption of vitamin B12 or other nutrients due to long-term PPI
use could play a role .

55. ENVIRONMENTAL RISK FACTORS
• Secondhand smoke – Associated with an increased risk of AD
• Risk was higher for in-home exposure compared with at-work exposure.

56. AIR POLLUTION
An increase in diffuse amyloid plaques and inflammation in the
olfactory bulb, hippocampus, and frontal lobes high levels of air
pollution, compared with adults living in smaller cities with lower levels
of air pollution
Similar findings have also been reported in children and young adults

57. PESTICIDES
• Several studies have implicated occupational or environmental
exposure to pesticides as a risk factor for AD .
• Serum dichlorodiphenyldichloroethylene (DDE)  levels of DDE were
3.8-fold higher in those with AD