Alzheimer’s Disease Pathogenesis

Role of Aging
DENHAM HARMAN
Department of Medicine, University of Nebraska College of Medicine,
984635 Nebraska Medical Center, Omaha, Nebraska 68198–4635, USA

ABSTRACT: Alzheimer’s disease (AD) is the chief cause of dementia, and

age is its major risk factor. The majority of cases (90–95%) are spo-
radic (SAD), and the remainder are familial (FAD). AD is characterized
by two brain lesions, intraneuronal fibrillary tangles and extracellular
plaques. The lesions are identical in SAD and FAD as well as to those in
persons with Down’s syndrome (DS). The same lesions are also observed
frequently in elderly non-demented individuals (E-ND). Both AD lesions
may stem from the normal progressive increases in oxidative stress (OxS)
throughout the body with age. Onset of dementia due to the accumulat-
ing lesions is around 40 years for DS, 40–60 years for FAD, over about
65 years for SAD, while that for E-ND is unknown. The lesions are made
clinically manifest with time by the normal increase with age of OxS,
“the dementia of old age,” or by a process specific for each AD category,
which enhances the normal OxS so as to lower the unknown onset age of
dementia for E-ND individuals to that associated with the AD category. A
plausible process can be advanced for each AD category. The hypothesis
suggests convenient, effective measures to prevent and treat, for exam-
ple, by decreasing brain OxS levels with oral antioxidants such as lipoic
or dehydroascorbic acids that are capable of passing the blood–brain
barrier.

KEYWORDS: aging; oxidative stress; mutations; Alzheimer’s disease;

Down’s syndrome

INTRODUCTION

Alzheimer’s disease (AD) is the chief cause of dementia.1 Age is the major
risk factor for the disease.1,2
The majority of cases3 (90–95% ) are sporadic (SAD). The remainder are
familial (FAD).3 Most FAD cases are associated with mutations in the gene
for presenilin 1 (PS1) on chromosome 14,4 some with mutations in the gene
Address for correspondence: Denham Harman, M.D., Ph.D., Department of Medicine, University
of Nebraska College of Medicine, 984635 Nebraska Medical Center, Omaha, Nebraska 68198-4635,
USA. Fax: 402-559-7330.
e-mail: vcerino@unmc.edu

Ann. N.Y. Acad. Sci. 1067: 454–460 (2006). 

C 2006 New York Academy of Sciences.

doi: 10.1196/annals.1354.065

454
HARMAN: ROLE OF AGING IN ALZHEIMER’S DISEASE 455

for presenilin 2 (PS2) on chromosome 1,5 while a few have mutations in the
gene for the amyloid precursor protein (APP) on chromosome 21.6
AD is characterized by two lesions1,2,7 : intraneuronal fibrillary tangles and
extracellular plaques. Major steps in pathogenesis have been summarized.8,9
Plaques are either diffuse or neuritic; Congo red stains the latter but not the
former. Diffuse plaques contain the majority of brain A peptides, mainly
A42. These plaques can form quickly—within a few days after head in-
jury,10 and early in life—as early as 12 years in patients with Down’s syndrome
(DS).11 Amyloid plaques, that is, neuritic plaques, stained by Congo red, are
formed by oxidative-polymerization free radical reactions involving preamy-
loid plaques.12 Amyloid formation is generally associated with the clinical
manifestations of AD.
The AD brain lesions in SAD and FAD are the same, and have the same
distribution pattern. Identical lesions are present in the brains of individuals
with DS,1,11 and are frequently observed in elderly non-demented persons
(E-ND).13 The latter suggests that AD lesions may be a normal accompaniment
of aging, and that in these E-ND individuals the number of lesions had not risen
to clinically significant levels before death.
Dementia onset, due to the accumulating AD lesions, is at around 40 years
for DS,11 40–60 years for FAD,3 over about 65 years for SAD,3 while that for
E-ND is not known. Lower dementia onset ages are associated with shorter
life spans.
Extensive studies of AD over the past 10–15 years have not resulted in a
generally accepted hypothesis on pathogenesis.14 Major emphasis has been
placed on the role of amyloid,9 the neurotoxin formed by the action of free
radicals on preamyloid.12

HYPOTHESIS ON PATHOGENESIS OF ALZHEIMER’S

DISEASE

The two lesions associated with AD are a normal part of aging; they stem
from the progressive increases in oxidative stress throughout the body with
advancing age. The lesions are made clinically manifest by time, “the dementia
of old age,” or by a process specific for each AD category, which enhances
OxS.

Formation of AD Lesions

Intraneuronal Fibrillary Tangles

The progressive increase throughout the body of more-or-less random free

radical reactions with advancing age (oxidative stress)—owing to the presence
456 ANNALS NEW YORK ACADEMY OF SCIENCES

of O 2 in the tissues, formation of superoxide radicals (SO) by mitochondria in

the course of normal metabolism and their spontaneous/enzymatic dismuta-
tion to H 2 O 2 ,15,16 decreasing availability of ATP for reductive synthesis, and
the likely progressive increases in tissue peroxidizability—should,8 like that
caused by menadione,17 eventually cause sustained elevation of calcium con-
centrations in the intracellular compartments. This leads18 to disruption of the
cytoskeleton and activation of calcium-dependent catabolic enzymes including
phospholipases, kinases, proteases, and endonucleases. In the case of neurons,
the foregoing may be exacerbated by overstimulation of receptors for excita-
tory amino acids.19 Some neurons may be expected to undergo apoptosis and
die.
Activation of kinases such as CaMK may be expected to progressively phos-
phorylate tau and thereby decrease the strength of its binding with micro-
tubules. The latter permits phosphorylated tau to self-assemble and form paired
helical filaments and, in turn, neurofibrillary tangles, while concomitantly the
destabilized microtubules break down. Accordingly, elevation of the intracel-
lular Ca2+ levels in cultured human cortical neurons20 causes ultrastructural
and antigenic changes in the cytoskeleton similar to those seen in neurons with
neurofibrillary tangles.

Neuritic Plaques

Conversion of the fibril form of the A peptides present in diffuse plaques

to that in amyloid probably normally increases slowly and progressively with
advancing age owing in part to increasing oxidative stress.8 At some age
in brain locations associated with elevated metabolic rates, that is, AD ar-
eas,8 the oxidative stress may exceed the threshold for the activation of mi-
croglial cells; this occurs in the late 20s or early 30s for those with DS,11
in a manner akin to the upregulation of the synthesis of cytokines IL-8 and
TNF- by the action of H 2 O 2 on dendritic cells.21 Then, free radicals formed
by activated microglia could serve to catalyze the oxidative conversion of
preamyloid in the microglial area to amyloid, and simultaneously initiate
the inflammation22 involved in neuritic plaque formation and neuronal cell
loss.
How apolipoprotein E4 lowers AD onset age is apparently not known. The
O 2 -mediated interaction between apoE423 and preamyloid (probably facilitated
by the presence of the two arginines in apoE424 ) suggests a possible explana-
tion: reaction of tissue O 2 with apoE4 may serve as a catalyst to further increase
the normally slow formation of oxidative changes in preamyloid, a process,
which results eventually in formation of amyloid. Thus, when H 2 O 2 -induced
microglial activation occurs, less time is required to complete the transfor-
mation. Hence, the age of onset of clinical symptoms of AD is decreased,
more so the longer the period of apoE4-associated changes prior to microglial
activation.
HARMAN: ROLE OF AGING IN ALZHEIMER’S DISEASE 457

Augmentation of the Innate Rate of AD Lesion Formation

Sporadic AD

Some of the accumulating mutation(s) in one or more of the approximately

1,000 mtDNA and nucDNA genes involved in mitochondrial biogenesis and
function25 —ignoring those involved in “the mitochondrial diseases”—would
be expected to have adverse effects on mitochondrial function, thereby increas-
ing oxidative stress and the rate of formation of AD lesions. The latter lowers
the onset age of the dementia of the E-ND group into that associated with
SAD.
Familial AD

APP, PS1, and PS2, as well as their mutated forms, undergo proteolytic pro-
cessing in the endoplasmic reticulum (ER) membrane.9 The calcium-buffering
activity of the ER is modulated by the ATPase calcium pumps,26 located in
the ER membrane, and by the associated Ca2+ release channels.27 Many com-
pounds influence ER calcium content,28 including (1) phospholamban, (2)
the ganglioside GM1 and GM3, (3) 6-gingerol and ellagic acid, (4) procaine,
caffeine, thapsigargin, and dantrolene, and (5) the erythrocyte isoenzyme of
acylphosphatase (this enzyme inhibits the Ca2+ pump by hydrolyzing the phos-
phointermediate formed during the catalytic cycle of the calcium ATPase).
It seems very likely that mutations in APP or the presenilins decrease ER
calcium buffering, in a manner akin to that of one or more of the substances
known to influence it, resulting in compensatory increases in other calcium
pools, particularly in mitochondria. The foregoing is strongly supported by
studies with cultured neurons.29
Increases in mitochondrial calcium content enhance SO formation, and
hence that of H 2 O 2. 30 This, in turn, lowers the age of onset of dementia of
the E-ND group and the life span.
Down’s Syndrome

Individuals with Down’s Syndrome disorder have three copies of chromo-

some 21 rather than the normal two.31
The early onset of AD in individuals with DS is attributed to an enhanced
rate of H 2 O 2 formation31 as a result of a defect in complex 1 of the respiratory
chain. Thus, the early appearance of AD in individuals with DS, as with SAD
and FAD, may be largely caused by a higher than normal rate of increase of
H 2 O 2 with age.
COMMENT

Oxidative stress increases with age; a major contributor to this is the H 2 O 2

derived from superoxide radicals formed by mitochondria in the course of
458 ANNALS NEW YORK ACADEMY OF SCIENCES

TABLE 1. Processes specific for each AD category.a

AD category Processes
SAD Accumulation of mutation(s) in one or more of the approximately 1,000
mtDNA and nucDNA genes involved in mitochondrial biogenesis and
function.
FAD Mutations in APP or the presenilins that downregulate ER
calcium-buffering capacity. This increases mitochondrial calcium
levels, resulting in enhanced H 2 O 2 formation.
DS Defective complex 1 of the mitochondrial respiratory chain.
a These augment to different degrees the innate cellular formation of hydrogen peroxide, thus lower-
ing the potential dementia onset age of the innate AD process into that associated with the AD category.

normal metabolism. Augmentation of the innate rate of H 2 O 2 formation by

a process (TABLE 1) specific for each AD category increases the rate of AD
lesion formation and accumulation, so as to lower the age of onset of dementia
of the EN-D group into that associated with the AD category.
The above suggests effective measures for prevention and treatment, for ex-
ample, by decreasing brain H 2 O 2 levels by oral antioxidants capable of passing
the blood–brain barrier such as lipoic acid32 or dehydroascorbic acid.33

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